AML Maintenance FAQs
Maintenance Strategies for AML Today: Experts Answer Frequently Asked Questions

Released: July 27, 2023

Amir T. Fathi
Amir T. Fathi, MD
Eytan M. Stein
Eytan M. Stein, MD
Amer Zeidan
Amer Zeidan, MBBS, MHS

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Key Takeaways
  • Patients with AML in remission after treatment can benefit from receiving oral azacitidine as maintenance therapy regardless of their measurable residual disease status.
  • Patients with FLT3-ITD‒positive AML should receive FLT3 inhibitor maintenance therapy following allogeneic stem cell transplantation for at least 2 years post transplant, with dose reduction or interruption preferred over discontinuation to manage adverse events. 

In this commentary, Eytan M. Stein, MD; Amir T. Fathi, MD; and Amer Zeidan, MBBS, MPH, answer audience questions from a recent live webinar titled “Critical Conversations in AML: Exploring Evidence-Based Maintenance Strategies” presented alongside the 2023 ASCO Annual Meeting.

How does postconsolidation measurable residual disease (MRD) status affect your decision regarding the use of oral azacytidine as maintenance therapy in patients with acute myeloid leukemia (AML)?
Patients with AML can benefit from oral azacitidine regardless of their MRD status. In the randomized phase III QUAZAR AML-001 trial (NCT01757535), oral azacitidine improved overall survival (OS) compared with placebo in patients who were both MRD positive (median OS: 14.6 months vs 10.4 months, respectively; HR: 0.69; 95% CI: 0.51-0.93) and MRD negative (median OS: 30.1 months vs 24.3 months, respectively; HR: 0.81; 95% CI: 0.59-1.12) at randomization. This significant OS benefit with oral azacitidine regardless of MRD status was confirmed in a multivariate analysis controlling for MRD status (HR: 0.74; 95% CI: 0.59-0.92). These data reassure us that even patients with MRD positivity can benefit from maintenance oral azacytidine, which is rare in AML, where MRD positivity typically indicates a poor prognosis. In the past, when discussing patients’ MRD positivity with them, the only thing we could say was that it was not a good thing prognostically and that predictively we did not have any treatment strategies to address it. Now, we can tell patients that there is an oral maintenance strategy that can improve their outcome based on the presence of MRD positivity.

Like everything else in leukemia, however, the consideration of MRD positivity is very nuanced. Instead of being viewed as positive or negative, there are different aspects to contemplate. For example, the type of MRD positivity in question affects how concerning it may be: Is it associated with preexisting clonal hematopoiesis of indeterminate potential, as revealed by the presence of what is referred to as a DAT mutation (ie, driver mutations involving epigenetic regulators DNMT3A, ASXL1, and TET2)? If so, it would be less concerning than if it were associated with an NPM1 or FLT3 mutation. When the patient became MRD positive also should be appraised. MRD positivity after consolidation in a patient who was MRD negative after induction could indicate impending relapse. Furthermore, patients with MRD positivity who go to transplant do not do very well. The use of oral azacytidine is important to consider in this subgroup of patients, but, again, it should be a very nuanced discussion.

In countries where oral azacitidine is unavailable, would parenteral azacitidine be an option for maintenance therapy?
There are data on injectable azacitidine as maintenance therapy. The randomized phase III HOVON97 trial (EudraCT 2008-001290-15) evaluated SC azacitidine vs observation post remission following ≥2 cycles of intensive chemotherapy in older patients (60 years and older) with AML or myelodysplastic syndromes with refractory anemia with excess blasts (N = 116). Patients receiving SC azacitidine had improved disease-free survival at 12 months (64% vs 42%; log-rank P = .04) and no difference in OS compared with observation. However, because of limitations of this study, we cannot officially recommend injectable azacytidine as maintenance therapy, and oral azacytidine is the standard of care. That said, injectable azacytidine is an option to try to maintain a patient with high-risk disease whom you are very concerned about and really would have liked to give oral azacytidine to, but it cannot be accessed. A hypomethylating agent such as azacitidine in combination with venetoclax could also be considered. Realistically, however, if you cannot get oral azacitidine, you also might not have access to venetoclax.

How long should a patient with FLT3-ITDpositive AML receive FLT3 inhibitor maintenance therapy following allogeneic stem cell transplantation? How do you manage adverse events (AEs) with long-term FLT3 inhibitor maintenance therapy?
In the randomized phase II SORMAIN, phase II RADIUS, and phase III MORPHO trials, the FLT3 inhibitors sorafenib, midostaurin, and gilteritinib, respectively, were given as maintenance therapy for 24 months. This is in line with what we recommend, which is to try to cover a patient for at least 24 months, because relapse after transplant most often occurs in the first 2-3 years. Then, at the 2-year mark, if the patient is doing very well—with no AEs, no financial toxicity, and no significant problems getting the drug—you can consider keeping them on the drug longer.

FLT3 inhibition in the posttransplant patient will require management of AEs such as those of the gastrointestinal tract, hand‒foot syndrome, nausea, liver issues, or decreased blood counts. To maintain patients on treatment through to the 2-year mark, we recommend taking a “something is better than nothing” approach: Instead of complete discontinuation, try pausing the drug, resuming at a lower dose, and seeing what a patient can tolerate. Dose interruptions also can be prolonged. Finally, if available, a switch to another FLT3 inhibitor can be considered. For example, if sorafenib becomes prohibitive in terms of tolerability, a patient could be switched to gilteritinib, which may be a bit better tolerated but is not without the potential for AEs.

Your Thoughts?
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