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medical literature landscape
An MRD-Guided Azacitidine Treatment Strategy
Delays Hematologic Relapse in MDS and AML
According to results from the phase
II RELAZA2 trial, minimal residual
disease (MRD)–guided treatment
with the hypomethylating agent
azacitidine delayed hematologic
relapse in patients with advanced
myelodysplastic syndromes (MDS)
or acute myeloid leukemia (AML),
with nearly half of MRD-positive
patients remaining relapse-free at
one year.
“Continuous MRD-negativity
translates into a very good prog-
nosis, and azacitidine can in turn
abrogate the dismal prognosis of
MRD-positive patients, especially
after allogeneic haemopoietic cell
transplantation (alloHCT),” lead
author Uwe Platzbecker, MD,
from University Hospital Lepzig in
Germany, told ASH Clinical News.
The findings of the trial were pub-
lished in Lancet Oncology.
The RELAZA2 trial enrolled 198
patients with advanced MDS (n=26)
or AML (n=172) from nine health
centers in Germany. All patients had
previously achieved complete remis-
sion (CR) following conventional
chemotherapy or alloHCT.
During a 24-month follow-up
period, patients who achieved a
CR were prospectively screened
for MRD by either quantitative
polymerase chain reaction for
mutant NPM1, leukemia-specific
fusion genes (DEK–NUP214,
RUNX1–RUNX1T1, CBFb–
MYH11), or analysis of donor-
chimerism in flow cytometry-sorted
CD34-positive cells (for alloHCT
recipients). MRD-positivity was
defined as a >1-percent increase
in NPM1 mutation or fusion
genes (RUNX1–RUNX1T1, CBFb–
MYH11, and DEK–NUP214) or a
≤80-percent reduction in CD34-
positive donor chimerism or in
the bone marrow or blood without
hematologic relapse.
Participants who experienced
disease relapse or severe, un-
resolved toxicity discontinued
study treatment.
During follow-up, 138 patients
were MRD-negative; 60 patients
remained MRD-positive and were
given subcutaneous azacitidine
75 mg/m 2 per day on days one
ASHClinicalNews.org
through seven of a 29-day cycle for
a total of 24 cycles. Patients who
achieved MRD-negativity were
able to de-escalate treatment to
azacitidine for five days every four
weeks for a total of six cycles.
Fifty-three MRD-positive pa-
tients were considered eligible for
pre-emptive azacitidine therapy.
Median age was 59 years (range =
52-69) and most patients (n=48;
91%) had AML.
At a median follow-up of 13
months (interquartile range =
5-22.8) from the start of MRD-
guided treatment, the study met
its primary endpoint: 31 patients
(58%) were alive and relapse-free
at six months after the start of
azacitidine treatment.
Nineteen of the 31 responders
(61%) developed MRD-negativity
and 12 (39%) remained MRD-
positive, but without disease relapse.
Of the patients who achieved
MRD-negativity, all were alive and
relapse-free at a median follow-
up of 23 months (range = 8-29).
However, seven patients (37%)
became MRD-positive at a median
of 280 days (range = 62-817) post-
azacitidine initiation.
Nearly half of patients
(n=24/53; 45%) continued to
receive azacitidine after the first six
treatment cycles, and seven (13%)
completed the entire two years of
protocol-specified treatment.
At one year after the patients
started azacitidine, the overall
survival (OS) rate was 75 percent
and the relapse-free survival (RFS)
rate was 46 percent among MRD-
positive patients. Compared with
MRD-positive patients, MRD-
negative patients had higher rates
of both 12-month OS (hazard
ratio [HR] = 3.1; 95% CI 1.4=6.7;
p=0.005) and RFS (HR=6.6; 95%
CI 3.7-11.8; p<0.0001), the authors
wrote.
“The observation that OS
of MRD-positive patients who
achieved a response with azaciti-
dine was similar to that of MRD-
negative patients suggests that
the treatment-mediated delay of
disease recurrence might be of
substantial benefit to patients,
as they can potentially be more
efficiently salvaged by subsequent
treatment,” they added.
Responses did not differ signifi-
cantly between patients who did or
did not undergo alloHCT (71% vs.
48%; p=0.097), but in a multivariate
analysis, the researchers observed
significant differences in RFS and
OS favoring MRD-low versus
MRD-high patients:
• RFS: HR=3.0 (95% CI 1.3-7.0;
p=0.0096)
• OS: HR=2.5 (95% CI 0.7-9.6;
p=0.17)
During the first six cycles of therapy,
infections and gastrointestinal tox-
icity were the most common grade
≥3 non-hematologic adverse events
(AEs). The most common grade
≥3 hematologic AEs included
neutropenia (85%), leukopenia
(32%), and thrombocytopenia (6%).
Dose reductions due to myelosup-
pression were required in nine
patients (17%) by the end of the
first six cycles of azacitidine and
most events were considered “both
reversible and manageable.”
One patient died because of
neutropenic infection at three
months after the first cycle of
azacitidine, which was considered
possibly related to treatment. No
other serious AEs were considered
related to the study drug.
Because an across-the-board
treatment recommendation in-
creases the risk of overtreatment in
patients who would never develop
MRD, the researchers suggested
that azacitidine could be used on
an individual, personalized pre-
emptive treatment basis based on
MRD detection. “The advantage of
this approach is to treat only pa-
tients at risk for relapse compared
with a flat maintenance strategy
which implies over-treatment of a
cohort of patients who will not re-
lapse,” Dr. Platzbecker concluded.
Limitations of the study in-
clude its lack of randomization and
a placebo or active control. The
small number of patients included
in the final analysis represented an
additional limitation of the study.
The authors report relationships
with Celgene.
REFERENCE
Platzbecker U, Middeke JM, Sockel K, et al. Measurable
residual disease-guided treatment with azacitidine to
prevent haematological relapse in patients with myelodys-
plastic syndrome and acute myeloid leukaemia (RELAZA2):
an open-label, multicentre, phase 2 trial. Lancet Oncol.
2018;19:1668-79.
Apixaban AVERTs Cancer-
Associated Venous
Thromboembolism
In the randomized, placebo-controlled
AVERT trial, investigators assessed the
safety and efficacy of apixaban thrombo-
prophylaxis in patients with cancer con-
sidered to be at intermediate- to high-risk
of developing a venous thromboembolism
(VTE). While the direct oral anticoagulant
resulted in a lower rate of VTE, it was
associated with a higher rate of major
bleeding episodes than placebo.
Marc Carrier, MD, from the University
of Ottawa and Ottawa Hospital Research
Institute, and co-authors reported their
findings in the New England Journal of
Medicine.
“The treatment of VTE with thera-
peutic anticoagulation is challenging in
patients with cancer because it often in-
volves daily injections of low-molecular-
weight heparin and is associated with
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