Past studies investigating the role of maintenance therapy in acute myeloid leukemia (AML) were unable to demonstrate an advantage in overall survival (OS). Consequently, maintenance therapy has not been an established practice in the treatment of AML.
The most effective post-remission therapy for AML continues to be allogeneic hematopoietic stem cell transplant (HSCT). However, allogeneic HSCT is not available to all patients with high-risk disease due to the lack of suitable donors or the potential toxicity and mortality associated with the procedure. Therefore, there is a significant need for strategies like effective maintenance in patients unable to undergo allogeneic HSCT, with the goal of improving OS. This review provides a summary of prior and ongoing approaches to maintenance therapy for AML.
Different maintenance therapy strategies for AML have been investigated for more than 40 years, including single agents and a combination of drugs or immune-based strategies. The earliest approaches to maintenance therapy of low-dose cytosine arabinoside, thioguanine, and anthracyclines were studied in randomized trials. Although some subgroups of patients experienced prolongation of remission duration and relapse-free survival, none of those trials were able to show a benefit in OS. Given the lack of OS benefit, maintenance therapy using chemotherapy is not recommended currently.
Immunotherapy, which includes therapeutic vaccines, cytokine therapy, lenalidomide, and immune checkpoint inhibitors, has probably been the most widely studied strategy to maintenance therapy in patients with AML.
With regard to therapeutic vaccines, there have been four randomized, controlled trials (RCTs) evaluating the effects of the bacillus Calmette-Guérin (BCG) vaccine as maintenance therapy in patients with AML. Of those studies, only one, which used a combination of BCG and irradiated allogeneic AML cells, showed an improvement in remission duration and OS. The remaining three RCTs found no outcome differences between maintenance and observation.
Similarly, RCTs on cytokine therapy as a maintenance strategy for AML have found no difference in five-year disease-free survival (DFS) or OS. As a result of the negative outcomes in literature and the unpleasant side effects associated with the administration of cytokines, these methods were abandoned.
Lenalidomide, although well tolerated, also failed to show an improvement in DFS and OS and is not considered to be effective in eradicating measurable residual disease (MRD).
Immune checkpoint inhibitors targeting programmed cell death-1 and cytotoxic T-lymphocyte antigen-4 have been used for the treatment of both solid tumors and certain hematologic malignancies, such as Hodgkin lymphoma. As monotherapy, they have demonstrated limited efficacy in patients with AML. The REMAIN trial is an ongoing study evaluating the efficacy of nivolumab maintenance versus observation in adults with AML in remission after chemotherapy.
Hypomethylating agents (HMA), including decitabine and azacitidine, have epigenetic activities. Both are now approved for the treatment of myelodysplastic syndromes in the United States but are also used as single agents for older patients with AML. So far, HMA maintenance does not seem to improve outcomes in younger patients with AML but does appear to be promising in older patients with AML who are not eligible for allogeneic HSCT. Based on the QUAZAR AML-001 trial, which showed an OS benefit for the oral formulation of azacitidine, it has been approved by the U.S. Food and Drug Administration (FDA) for continued therapy in patients with AML in remission.
Small-Molecule Targeted Therapies
Small-molecule targeted agents have been the focus of several studies and include FLT3 inhibitors and the BCL-2 inhibitor venetoclax.
FLT3 inhibitors used as maintenance therapy in patients with FLT3-mutated AML include midostaurin, sorafenib, and gilteritinib. Based on the phase III RATIFY trial, midostaurin was approved by the European Medicines Agency; however, it has not been approved by the FDA. In the SORAML trial, patients who received sorafenib had an improved event-free survival (EFS) of 21 months versus 9.5 months in the placebo arm. There was no improvement in OS. Gilteritinib was shown to improve outcomes in relapsed and refractory FLT3-mutated AML, and an ongoing, phase III, randomized trial is comparing DFS in patients with FLT3-mutated AML who were randomized to receive either gilteritinib or placebo for an 11-year period after completion of induction/consolidation chemotherapy.
Venetoclax has shown improved outcomes in combination with HMA for older patients with newly diagnosed AML and is currently being tested in a phase II trial in which patients are treated with azacitidine and venetoclax until MRD negativity is achieved, followed by venetoclax maintenance.
In a multicenter, prospective, randomized, open-label, phase III study, 330 patients were enrolled and randomized to norethandrolone versus placebo. Of those, 165 patients received norethandrolone. The results showed an improved DFS, EFS, and OS at one year compared with the placebo arm. In this study, the beneficial effects of norethandrolone became evident after one year and were apparent in those who had not relapsed within one year after achieving complete response (CR).
Although allogeneic HSCT following induction and consolidation therapy in AML is highly effective in reducing the risk of relapse, unfortunately, up to 40% of patients will relapse post-HSCT and face a dismal prognosis. Maintenance therapy is intended to prolong remission and facilitate a graft-versus-leukemia effect to eradicate residual leukemia cells.
Post-transplant maintenance therapy with decitabine in combination with recombinant granulocyte colony-stimulating factor (G-CSF) was studied in an open-label, multicenter, phase II trial that included 204 patients with AML who were MRD-negative following allogeneic HSCT. The two-year cumulative relapse rate was reduced in the treatment arm compared with placebo (38.3% vs 15.0%), and the OS was superior with G-CSF and decitabine compared with placebo (85.8% vs 69.7%).
Various FLT3 inhibitors, including sorafenib, midostaurin, and quizartinib have also been investigated in the post-transplant setting as maintenance options. Several studies reported potential benefits with those inhibitors in the setting of post-allogeneic HSCT maintenance therapy.
Need for Effective Post-Remission Strategies
Despite decades of investigation, optimal maintenance strategies for the management of AML are lacking, and there are insufficient data to support routine maintenance therapy. While the introduction of targeted therapies applied in combination with chemotherapy has improved the CR rate, the rate of relapse has remained unchanged, a fact that points to the most common cause of treatment failure in the post-consolidation setting. It is critical to consider that maintenance therapy is associated with increasing costs, exposure to long-term drug toxicity, and impaired quality of life. Moreover, there is the risk of overtreating a subset of patients who might have been cured with induction and consolidation therapy, which underlines the importance of defining the patient population that will benefit from receiving maintenance therapy. There is an urgent need to identify effective post-remission strategies, with the aim of improving DFS and OS.