CLINICAL NEWS
Azacitidine
Maintenance Improves
Survival in Older
Patients with Newly
Diagnosed AML
Older patients with acute myeloid leukemia
(AML) in complete remission (CR) who
received maintenance therapy with subcutane-
ous 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 azaciti-
dine 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 neutro-
phil count >0.5×10 9 /L and a platelet count
>50×10 9 /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 re-
sponse, with a median follow-up of 41.4 months
(range not reported). These participants were
randomized to receive 12 cycles of azacitidine 50
mg/m 2 for 5 days every 4 weeks (n=56) or obser-
vation 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 ≥100×10 9 /L.
Maintenance treatment with azacitidine
appeared to be feasible, with 63 percent of
patients in the treatment arm (n=37/56) com-
pleting azacitidine treatment. Adherence to the
schedule also was 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 pa-
tients 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 ob-
servation group and 75 percent of those in the
ASHClinicalNews.org
azacitidine treatment group did not experience
any serious AEs,” the authors reported.
However, azacitidine treatment was as-
sociated with higher rates of DFS (primary
endpoint; measured from the time of random-
ization) 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
≥100×10 9 /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 se-
condary 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. “Ap-
parently, 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 re-
cruitment, 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.
REFERENCE
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]
PERSPECTIVES
“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, hematolo-
gists 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 second-
ary 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 adminis-
tration, drug availability, efficacy, and AE pro-
files 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
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