Azacitidine Maintenance Improves Disease-Free Survival in Older Patients with Newly Diagnosed AML

Older patients with acute myeloid leukemia (AML) in complete remission (CR) who received maintenance therapy with subcutaneous azacitidine had longer disease-free survival (DFS), compared with patients who received observation alone, according to results from the final analysis of the phase III HOVON-97 (Dutch-Belgian Hemato-Oncology Cooperative Group) study published in Blood.

“In general, CRs obtained after remission-induction chemotherapy in patients older than 60 years are short-lived, [and] the prevention of relapse is the major therapeutic challenge in [this setting],” the authors, led by Gerwin Huls, MD, PhD, from University Medical Center Groningen in the Netherlands, wrote. “This study provides the first prospective evidence for the feasibility and effectiveness of azacitidine maintenance in [these patients].”

HOVON-97 included older patients (≥60 years) with a confirmed diagnosis of AML or myelodysplastic syndrome–refractory anemia with excess blasts who had CR or CR with incomplete hematologic recovery after two or more cycles of intensive chemotherapy. Patients also were required to have an absolute neutrophil count >0.5×109/L and a platelet count >50×109/L.

Accrual on the study was slow, and the study was terminated before the accrual of the planned 126 patients.

A total of 116 patients (median age = 69 years; range = 60-81 years) were evaluable for response, with a median follow-up of 41.4 months (range not reported). These participants were randomized to receive 12 cycles of azacitidine 50 mg/m2 for 5 days every 4 weeks (n=56) or observation with no further treatment (n=60).

The authors reported that patient and disease characteristics were balanced between the treatment and observation arms: 23 percent and 16 percent, respectively had unfavorable-risk cytogenetics and 75 percent and 68 percent had platelet counts ≥100×109/L.

Maintenance treatment with azacitidine appeared to be feasible, with 63 percent of patients in the treatment arm (n=37/56) completing azacitidine treatment. Adherence to the schedule was also high, they added, noting that “on average, 90 percent of the azacitidine cycles were given full dose according to schedule.”

Eighty-six percent of azacitidine-treated patients were red blood cell or platelet transfusion-independent, compared with 92% and 93% in the observation arm (p value not reported), and a low proportion of patients required an overnight hospitalization in both groups (14% and 8%).

“The number of adverse events (AEs) and serious AEs were also comparable between both arms: 93 percent of patients in the observation group and 75 percent of those in the azacitidine treatment group did not experience any serious AEs,” the authors reported.

However, azacitidine treatment was associated with higher rates of DFS (primary endpoint; measured from the time of randomization) compared with observation:

  • 24-month DFS: 44% vs. 20%
  • 36-month DFS: 32% vs. 16% (p=0.04)

A multivariate analysis adjusting for poor-risk cytogenetic abnormalities and platelet count ≥100×109/L at time of enrollment confirmed this improvement in DFS (hazard ratio = 0.62; 95% CI 0.41-0.95; p=0.026).

Despite this improvement in DFS, there was not a noticeable improvement in the secondary endpoint of overall survival (OS) at 12 months (84% with azacitidine vs. 70% with observation; p=0.69).

During follow-up, 87 patients relapsed, and 86 received rescue treatment. The OS was significantly improved in patients who received rescue treatment (p<0.001), as the investigators expected, and the effects of rescue treatment were observed in both treatment arms. “Apparently, maintenance with azacitidine did not result in resistance for rescue treatment,” they concluded, further supporting the feasibility of this approach.

Limitations of the study include its slow recruitment, early termination, small number of patients included in the final analysis, as well as the lack of an active treatment comparator arm. The researchers also cited the lack of data on the molecular characterization of AML blasts, which resulted in the inability to examine the effects of maintenance therapy with azacitidine in specific molecular subgroups.

The authors report relationships with Celgene.


Huls G, Chitu DA, Havelange V, et al. Azacitidine maintenance after intensive chemotherapy improves DFS in older AML patients. Blood. 2019 January 10. [Epub ahead of print]

Because this study demonstrated that the use of maintenance azacitidine was feasible, tolerable, and effective in older patients with AML who have achieved remission with an intensive induction regimen, hematologists and hematologic oncologists now have additional evidence for using epigenetic agents in the maintenance setting for these patients. It was interesting that maintenance azacitidine resulted in a disease-free survival benefit but not an OS benefit; however, the authors noted that the trial was not powered to detect an OS benefit (which was a secondary objective) and that a higher proportion of patients in the control group received salvage treatment while on study.

In clinical practice, patients and their physicians will have to determine whether maintenance is appropriate and, if so, which maintenance regimen is the optimal choice. The best maintenance choice for patients aged 60 or older remains unclear, as there are differences in convenience, route of administration, drug availability, efficacy, and AE profiles between various maintenance regimens. Also, observation after complete remission remains a viable option for older patients.

Edward Allan R. Sison, MD
Baylor College of Medicine
Texas Children’s Hospital
Houston, TX