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On Location 2018 ASH Annual Meeting
Continued from page 38
treatment,” Dr. Garcia-Manero stressed. The
most commonly reported grade 3/4 adverse
events (AEs) in both cohorts included
infection, rash, musculoskeletal pain, and
transaminitis.
The safety and efficacy results observed
in this trial suggest that “the incorporation
of immune checkpoint inhibitor therapy is
feasible in patients with MDS,” Dr. Garcia-
Manero concluded. There was a potential
relationship between PD1 expression and
response, but he noted that this needs to be
explored further. The results also need to be
confirmed in larger randomized trials in the
frontline and relapsed settings, he added.
Atezolizumab Plus Azacitidine
Next, Aaron Gerds, MD, from Cleveland
Clinic’s Taussig Cancer Institute, shared
findings from a trial evaluating atezolizumab,
with or without azacitidine, in patients with
HMA-naïve, higher-risk MDS (defined as
intermediate, high, or very high-risk per
the Revised International Prognostic Sco-
ring System) or who had disease that was
relapsed/refractory to prior HMA therapy.
After researchers observed a high number
of deaths within the first three treatment
cycles in the HMA-naïve cohort, the study
was terminated early.
This phase Ib trial enrolled 42 adult
patients into three cohorts:
• cohort A1: HMA-failure MDS and
atezolizumab alone (n=10)
• cohort B1: HMA-failure MDS and
atezolizumab plus azacitidine for
6 cycles, followed by atezolizumab
maintenance alone (n=11)
• cohort C1/C2: HMA-naïve MDS and
atezolizumab plus azacitidine until
clinical benefit (n=21)
In the safety analysis, grade 3/4 AEs were
common, occurring in 50 percent (n=5/10),
91 percent (n=10/11), and 57 percent
(n=12/21) of patients in cohorts A, B, and
C1/2, respectively. Immune-related AEs
included infusion-related reactions and
hypothyroidism in cohort A and rash and
hemolysis in cohorts B and C.
There were 21 deaths across the three
cohorts: seven in cohort A, eight in cohort
B, and six in cohort C1/C2. Most deaths
were related to progressive disease in
cohorts A and B, but all deaths in cohort C
were attributed to AEs.
Deaths occurred early in the HMA-
naïve patients in cohort C1/C2, Dr. Gerds
reported. All six occurred within the first
three treatment cycles, three of which oc-
curred within the first treatment cycle.
When asked about potential mecha-
nisms for the increased toxicity with
atezolizumab, compared with other
immunotherapies, Dr. Gerds noted that
there was “no clear biologic plausibility
[to explain this association], although the
fact that antibiotic prophylaxis was left to
investigator discretion may have led to an
increased infection risk.”
No patients with HMA-failure MDS
responded to treatment with atezolizumab
(cohort A), while only one patient with
HMA-failure MDS responded to treat-
ment with atezolizumab plus azacitidine
(cohort B). In cohort C, however, 13
patients responded to treatment, for an
ORR of 62 percent.
Median OS was not reached in cohort C
but was 177 days in cohort A and 361 days in
cohort B. Six patients with HMA-naïve MDS
are continuing to receive the atezolizumab/
azacitidine combination, and the investiga-
tors also are continuing to follow patients
who discontinued the study early to identify
potential markers of response.
“The number of deaths we saw early
was certainly concerning,” Dr. Gerds said.
However, given the responses to atezoli-
zumab plus azacitidine seen in the HMA-
naïve population, he added that “a better
understanding of the different toxicity
profiles observed between HMA-naive and
HMA-failure patients with higher-risk MDS
patients is crucial for future developments of
this combination.”
The authors of the first trial report rela-
tionships with Bristol-Myers Squibb, which
supported the trial. The authors of the second
trial report relationships with Roche, which
supported the trial.
REFERENCES
Garcia-Manero G, Sasaki K, Montalban-Bravo G, et al. A phase II study of
nivolumab or ipilimumab with or without azacitidine for patients with
myelodysplastic syndrome (MDS). Abstract #465. Presented at the 2018
ASH Annual Meeting, December 2, 2018; San Diego, CA.
Gerds A, Scott B, Greenberg P, et al. PD-L1 blockade with atezolizumab in
higher-risk myelodysplastic syndrome: an initial safety and efficacy analysis.
Abstract #466. Presented at the 2018 ASH Annual Meeting, December 3,
2018; San Diego, CA.
Transplant or No Transplant for
Older, Fit Patients With MDS?
Hematopoietic cell transplantation (HCT)
with reduced-intensity conditioning
improved overall survival (OS) in older
patients with advanced myelodysplastic
syndromes (MDS), compared with OS in
patients who did not undergo transplant,
according to a non-randomized report
from the Myelodysplastic Dysplastic Syn-
dromes Transplant-Associated Outcomes
(MDS-TAO) study.
The results, which were presented
at the 2018 ASH Annual Meeting by
Gregory A. Abel, MD, MPH, from Dana-
Farber Cancer Institute in Boston, suggest
that transplant should be considered for
older, fit patients.
This observational study included
patients between the ages of 60 and 75
with advanced MDS or chronic mono-
myelocytic leukemia who presented at
Dana-Farber. Patients who were con-
sidered eligible for HCT, met the study
inclusion criteria (int-2/high disease per
the International Prognostic Scoring Sys-
tem [IPSS], poor-risk cytogenetics, or the
severe cytopenia/platelet or red blood cell
transfusion–dependence), and were will-
ing to undergo transplant were enrolled in
the trial.
Between May 2011 and May 2018, 290
patients were enrolled. 24 patients had
fewer than 90 days of follow-up and were
excluded from the final analysis.
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ASH Clinical News
The median age among the remaining
266 patients was 69 (range = 60-75 years),
and most had favorable-risk cytogenetics
(53%). Most patients had either int-1 or
int-2 disease (44% and 36%, respectively).
A total of 102 participants underwent
transplant (within a median of 4.6 months
from enrollment; range not reported) and
164 underwent treatment without HCT.
The researchers found that patients who
had higher-risk disease (int-2/high on
the IPSS) at baseline were more likely to
undergo HCT (65% vs. 35%; p=0.0003),
after adjusting for age, gender, Eastern
Cooperative Oncology Group (ECOG)
performance status, IPSS stage and cyto-
genetics, and year of trial consent.
The study used a landmark analysis
at five months to estimate OS among
patients who were alive for at least five
months and received HCT, versus patients
who did not (landmark cohort).
During the study observation period,
45 patients in the HCT group and 98 in
the non-HCT group had died, leaving a
final cohort of 123 surviving patients.
The median follow-up among sur-
vivors was 31 months (range = 1.9-84
months), and the median follow-up for
patients alive and not yet transplanted
(n=66) was 24 months (range = 1.9-82
months).
In a multivariable analysis, patients
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who underwent transplant had a signifi-
cantly lower risk of death (hazard ratio
[HR] for OS = 0.63; 95% CI 0.42-0.96;
p=0.03). The investigators evaluated other
patient characteristics (disease stage,
ECOG score, age, gender, year of consent)
and found that only poor-risk cytoge-
netics were associated with worse OS
(HR=1.86; 95% CI 1.15-3.00; p=0.006);
“In this [study] of fit elderly patients
with advanced MDS, a treatment strategy
that included HCT was associated with
better OS,” the authors concluded. The
study’s findings are limited by the lack
of a randomized design, the potential
for selection bias, and the researchers
noted that subgroup analyses to evaluate
whether molecular characteristics or other
disease factors affect survival outcomes
are ongoing.
The authors report relationships with
H3 Biosciences, Celgene, Arog, AbbVie,
Agios, Novartis, ARIAD, Blueprint
Medicines, GlycoMimetics, Millennium,
Prometheus, and Miltenyi Biotech. ●
REFERENCE
Abel GA, Kim HT, Steensma DP, et al. Survival after hematopoietic stem
cell transplantation in an older, fit cohort of patients with advanced
myelodysplastic syndromes: the MDS-TAO study. Abstract #972. Presented
at the 2018 ASH Annual Meeting, December 3, 2018; San Diego, CA.
February 2019