General AML

Monthly editorial theme │ Maintenance therapy for AML

Disease relapse is one of the main issues in the treatment of patients with acute myeloid leukemia (AML). Although most patients will achieve remission following standard induction chemotherapy, a high proportion will relapse and not reach long-term survival. For some of these patients, consolidation therapy with or without allogeneic stem cell transplantation (allo-SCT) will decrease the risk of relapse but not for the majority.1,2 Maintenance therapy has been proven very efficacious at improving long-term patient outcomes and reducing relapse in the acute lymphoblastic leukemia (ALL) setting.1 Thus, research into the role of maintenance therapy for the treatment of AML is crucial and has attracted a lot of clinical interest.

VIDEO INTERVIEW: Selina Luger | SOHO 2019 | What is the role of maintenance therapy for patients with AML?

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).1,2 Nevertheless, 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 HOVON97 trial. 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 here by 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 presented on 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-AMLE phase III randomized trial were also presented on December 07, 2019 at ASH. This trial assessed the efficacy of azacitidine versus best 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 SORMAIN trial. The results of this phase II trial have been summarised by the AGP here. In the interview shown below, Prof. Andreas Burchert noted 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.

VIDEO INTERVIEW: Andreas Burchert | ASH 2018 | Key highlights of the SORMAIN trial 

The phase III trial, MORPHO (NCT02997202) is currently investigating the efficacy of the FLT3 inhibitor, gilteritinib as maintenance therapy following chemotherapy and allo-SCT in the FLT3-ITD positive AML setting. Another aim of this study is to assess whether MRD can predict the AML patient population that could benefit the most from maintenance therapy. The study design of this trial has been further discussed with Prof. Mark Lewis in his AGP interview below.

VIDEO INTERVIEW: Mark Levis | ASCO 2018 | Maintenance therapy with gilteritinib in FLT3-ITD+ AML

Moreover, another FLT3 inhibitor, quizartinib, has been recently identified in a phase I trial (NCT01468467) to have preliminary efficacy and acceptable tolerability, as maintenance agent in patients with FLT3-ITD positive AML.

Interestingly, the FLT3 inhibitor midostaurin, has shown to improve patient outcomes when used as front-line treatment in combination with standard chemotherapy, as well as maintenance after that for up to 12 cycles in responding patients. The data for midostaurin were provided from the phase III trials RATIFY, which has been summarised by the AGP here.

B. MRD assessment to guide treatment decisions

Except for FLT3-ITD-trageted therapies, risk-adapted maintenance therapies based on MRD assessment have a great potential for improving the outcomes of patients with AML. Currently, there are limited data to guide the use of maintenance therapy dependent on the MRD status. The phase II trial RELAZA2 that has been summarised here, evaluated the role of azacitidine in the setting of MRD-guided pre-emptive therapy in order to prevent or delay relapse in patients with MDS or AML after chemotherapy and allo-SCT. The results of this study were discussed with Prof. Uwe Platzbecker in his AGP interview below.

VIDEO INTERVIEW: Uwe Platzbecker | ASH 2017 | MRD guided treatment in AML: the RELAZA2 trial

This study demonstrated that MRD monitoring can identify patients who are likely to relapse, and MRD-guided maintenance with azacitidine could be an effective strategy to delay relapse. This supports the prognostic importance of MRD monitoring in AML and will hopefully serve as a platform for future studies combining MRD with treatment guidance not only at the maintenance but also the front-line setting. More information on the role of MRD in guiding treatment following allo-SCT in patients with AML can be found in our descriptive review here.

Conclusion

To date, there is a lot of variability on how MRD is incorporated into clinical decisions. It is certain that prospective randomized trials that will assess MRD evaluation pre- and post-transplant to guide the use of therapy.

The beneficial role of maintenance therapy for patients with AML is becoming increasingly clear, nevertheless the most beneficial use of maintenance remains to be further defined. Who benefits from maintenance with HMA or targeted therapies? Should maintenance agents be given before and after allo-SCT or maybe after combination therapy with HMAs plus venetoclax? Further investigation with large randomized clinical trials is needed to address these questions and to confer the right time and patients that will benefit the most from maintenance therapy.

References
  1. McMahon, C. M. & Luger, S. M. Maintenance therapy in acute myeloid leukemia: What is the future? Semin. Hematol. 2019 Apr; 56:102–109. DOI: 10.1053/j.seminhematol.2018.08.006
  2. Molica, M. et al. Maintenance therapy in AML: The past, the present and the future. Am. J. Hematol. 2019 Aug 19; 94:1254–1265. DOI: 10.1002/ajh.25620

Expert Opinion

“Maintenance therapy is about to become an integral part of treatment for patients with AML. There is a huge unmet need for those patients who do not receive allogeneic transplant after intensive chemotherapy as they need well tolerated treatments, which suppress the growth of remaining leukemia cells and push out the time of their relapse. The Quazar study has convincingly demonstrated just that.”

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