Promising maintenance agents
A good maintenance agent needs to confer two things: a) tolerability with low toxicity, as well as b) efficacy at preventing disease re-occurrence. Numerous candidate agents have been assessed as maintenance therapy for AML over the years including, cytokines, vaccines, checkpoint inhibitors, FMS-like tyrosine kinase 3 (FLT3
)inhibitors, and hypomethylating agents (HMAs).
1,2Nevertheless, until recently there has been a shortage of large randomized prospective trials with patients receiving the current standard of care first-line therapy to validate the role of these.
Hypomethylating agents for maintenance
The first strong evidence on the potential of HMAs as maintenance agents for AML was given by the
HOVON97trial. This randomized, phase III study evaluated the efficacy of azacitidine maintenance in older patients (≥60 years) with AML or myelodysplastic syndrome with refractory anemia with excess blasts (MDS-RAEB), who had achieved remission following at least two cycles of intensive chemotherapy. The final analysis of this trial has been summarised
hereby the AGP, and concluded that azacitidine maintenance leads to superior disease-free survival than no maintenance therapy at all, in newly diagnosed, heavily treated older patients with AML.
The results of the HOVON97 trial have very recently been confirmed by the announcement of the primary results of the larger, randomized, phase III trial
QUAZAR. This study investigated the efficacy of oral azacitidine in 472 patients with newly diagnosed AML, who achieved remission with induction chemotherapy. Top-line results from the study demonstrated that maintenance with azacitidine resulted in significant improvements in overall survival and relapse-free survival when compared to placebo. In addition, azacitidine maintenance was reported to be well tolerated with no unexpected safety events occurring. More information on the study design of QUAZAR and the primary data announcement can be found
here. The data from this phase III study will be presented at a future meeting and regulatory submissions are anticipated in the first half of 2020.
Currently, another HPA, decitabine, is being investigated as a potential maintenance agent for AML. This ECOG randomized phase III trial (
E2906) is underway and will examine the efficacy of decitabine maintenance after clofarabine- or daunorubicin plus cytarabine-based front-line chemotherapy in older patients with newly-diagnosed AML. Preliminary results from this trial
were presentedon December 07, 2019 at the
American Society of Hematology (ASH) Annual Meeting. These indicated that decitabine maintenance for one year after intensive chemotherapy improves the overall survival and disease-free survival (DFS) of older patients with AML. Moreover, decitabine maintenance also prolonged the survival of the AML subpopulation with the FLT3-internal tandem duplication (ITD).
The final results of the
QoLESS AZA-AMLEphase III randomized trial
were also presentedon December 07, 2019 at ASH. This trial assessed the efficacy of azacitidine
versusbest supportive care in older patients with AML (>60 years of age), who were in remission following induction and consolidation chemotherapy. The outcomes of this study showed that azacitidine maintenance in elderly patients with AML is well-tolerated and that in patients over 73 years of age it significantly prolongs DFS.
Although the best maintenance therapy for patients with AML is not yet completely clear, all the above encouraging data predict the incorporation of maintenance agents in the standard of care protocols. Moreover, target-directed and risk-adapted maintenance therapies will also provide further insights into the role of maintenance therapy in AML. Currently, a lot of research has been targeted at specific AML subpopulations, including FLT3-ITD positive patients and at the role of measurable residual disease (MRD) in maintenance treatment guidance.
Targeted therapies for maintenance
A. FLT3-ITD positive AML
Using FLT3 inhibitors as maintenance therapy has shown promising results in patients with FLT3-ITD positive AML. The maintenance potential of the FLT3 inhibitor sorafenib for patients that have already received consolidation and allo-SCT was initially indicated by the results of the
SORMAINtrial. The results of this phase II trial have been summarised by the AGP
here. In the interview shown below,
Prof. Andreas Burchertnoted that the data from the SORMAIN trial demonstrated for the first time that FLT3 inhibition after allo-SCT is feasible and significantly reduces the risk of relapse or death while improving the survival of patients with FLT3-ITD positive AML. He further added that this study has practice-changing implications that will establish a new treatment paradigm for AML.