Treating MRD With Azacitidine in Patients With High-Risk AML and MDS

For 58 percent of patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) at high risk for relapse, treatment of minimal residual disease (MRD) with azacitidine was feasible, according to results from the prospective RELAZA2 trial.

“Monitoring of MRD in morphologic complete remission has been shown to allow for predicting subsequent hematologic relapse, thus opening a window for preemptive therapeutic interventions,” said lead author Uwe Platzbecker, MD, from University Hospital Carl Gustav Carus in Dresden, Germany, during his presentation of the results at the 2017 ASH Annual Meeting. “[Findings from this trial] support the prognostic importance of MRD in AML and may serve as a platform for future studies combining hypomethylating agents with novel targeted therapies.”

Researchers enrolled 205 patients from 2011 to 2015 at 11 centers in Germany: 27 people had advanced MDS and 178 had AML. All experienced complete remission (CR) following either conventional chemotherapy only (n=58) or allogeneic hematopoietic cell transplantation (alloHCT; n=147).

Investigators monitored MRD (measured by level of NPM1 mutation or leukemia-specific fusion genes in bone marrow or peripheral blood, or CD34-positive donor chimerism in alloHCT-treated patients) starting at day 56 after completion of last therapy, followed by monthly intervals for two years.

Fifty-three of the 205 patients with CR had measurable MRD above the predefined threshold for “imminent relapse” and went on to receive preemptive azacitidine (75 mg/m2 subcutaneously on days 1-7, followed by an additional 6-12 cycles, for up to 18 additional months).

Median age of the 53 treated patients was 59 years (range = 52-69 years); 48 (91%) had AML and five (9%) had MDS.

After completion of the initial six cycles of azacitidine, 31 patients (58%) were still in hematologic CR (primary endpoint). This included 19 participants (36%) with “major response,” defined as a decline of MRD below a predefined threshold (NPM1 mutation level ≤1% or CD34-positive donor chimerism ≥80%). Another 12 patients (23%) had “minor response,” defined as MRD of CD34-positive donor chimerism <80 percent or mutation level ≤1 percent but no relapse.

The overall response rate varied between patients with and without antecedent alloHCT (71% and 48%, respectively; p=0.007).

Twenty-two participants (42%) relapsed after a median of three cycles of azacitidine (range not provided). After six months, 24 patients continued to receive azacitidine, for a median of nine subsequent cycles (range not provided). In eight of those patients, hematologic relapse occurred at a median of 397 days following initial MRD detection (range not provided).

At a median follow-up of 13 months (range not provided), secondary endpoints of overall and progression-free survival rates were 76 percent and 42 percent, respectively.

Preemptive treatment with azacitidine also appeared to be well tolerated. Infections and pneumonia were the most commonly reported severe adverse events during the initial six cycles (n=4 and n=3, respectively).

“We still saw some late relapses in these patients, even after continuation of azacitidine,” Dr. Platzbecker added, “but the data look promising – especially in patients with relapse after transplantation.”

The open-label design and relatively small number of patients are limitations of the study.

The authors report financial relationships with Celgene, the manufacturer of azacitidine.


Platzbecker U, Middeke JM, Sockel K, et al. Minimal-residual disease guided treatment with azacitidine in MDS/AML patients at imminent risk of relapse: results of the prospective RELAZA2 trial. Abstract #565. Presented at the 2017 American Society of Hematology Annual Meeting, December 11, 2017; Atlanta, GA.