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achieved complete response or stringent complete
response. In addition, 92% of responders
achieved minimal residual disease negativity in
the bone marrow on or before day 1 of cycle 4.
All responses occurred in the higher-dose
groups (>3 mg) and there appeared to be a
dose-response relationship, the investigators
observed. Among the 9 patients who were given
the CC-93269 10 mg dose, the overall response
rate was 89%, including 44% complete response
or stringent complete response.
As the data cutoff, 11 of the 13 responses were
ongoing, with a duration of response ranging
from 5.3 to 40.6 weeks.
“These early data show remarkable activity
in highly refractory, heavily pretreated patients
with multiple myeloma,” Dr. Costa said, adding
that the recommended phase II dose has not yet
been reached.
While the study investigators called these
findings “promising,” they are limited by the small
patient population and lack of a comparator arm.
The authors report relationships with Celgene,
which sponsored the trial.
Reference
Costa L, Wong SW, Bermudez A, et al. Interim results from the first phase 1 clinical
study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269
in patients (pts) with relapsed/refractory multiple myeloma (RRMM). Abstract
S205. Presented as part of EHA25 Virtual, June 12, 2020.
CC-486 Improves Transfusion Independence in Myelodysplastic Syndromes,
but Adverse Events Are Common
For patients with lower-risk myelodysplastic syndromes
(MDS) and both red blood cell (RBC) transfusion-dependent
anemia and thrombocytopenia,
CC-486, an oral formulation of the hypomethylating
agent (HMA) azacitidine, significantly
improved RBC transfusion independence compared
with placebo, according to findings from a
phase III study presented at EHA25Virtual, the
remotely held 25th European Hematology Association
Annual Congress. However, the study was
closed early at the recommendation of the trial’s
independent Data Safety Monitoring Committee
(DSMC) due to a higher incidence of deaths in the
active therapy arm.
Lead investigator Guillermo Garcia-Manero,
MD, of the University of Texas MD Anderson
Cancer Center, told ASH Clinical News that he
believes, based on these findings, that an oral HMA
will eventually become standard in both lowerand
high-risk MDS – conditions where treatment
options are currently limited.
The study enrolled adults with International
Prognostic Scoring System lower-risk MDS
and anemia that required an average of ≥2 units
of RBCs every 28 days for ≥56 days. Only those
patients with 2 platelet counts of ≤75×10 9 /L that
were taken ≥21 days apart were considered eligible
for study entry. Additional inclusion criteria were:
• thrombocytopenia (sustained for ≥21 days)
within 14 days of randomization
• Eastern Cooperative Oncology Group
performance status of 0-2
• A total of 216 patients were randomly
assigned to receive:
• oral CC-486 at a starting dose of 300 mg daily
(n=107)
• identically matching placebo (n=108)
Both the active treatment and placebo were
administered with best supportive care on days 1
through 21 of each 28-day treatment cycle.
The baseline characteristics were well balanced
between the treatment arms, Dr. Garcia-Manero
said. The median age of the cohort was 74 years
(range = 30-89), and the median hemoglobin
was 8.1 g/dL (range = 5.4-10.9). Participants had
median platelet counts of 25×10 9 /L (range = 5-73)
and the median transfusion requirement was 6.7
units over 56 days.
He reported that all randomized patients
either completed ≥12 months of treatment or discontinued
the study before 12 months at time of
data cutoff. The median treatment durations were
5 cycles for CC-486 (range = 1-70) and 6 cycles for
placebo (range = 1-69).
An oral hypomethylating
agent may eventually
become standard in both
lower- and high-risk MDS
– conditions where
treatment options are
currently limited.
Outcomes were assessed at cycle 6. Per study
protocol, patients who achieved transfusion independence
or a ≥50% reduction in transfusion
requirements, had hematologic improvement in
erythroid and platelet lineages, and had no evidence
of progressive disease stopped treatment
and were followed to measure survival, progression
to acute myeloid leukemia, development of
second primary malignancies, and need for other
MDS treatments. Participants who remained
transfusion dependent or had inadequate response
at cycle 6 discontinued treatment.
At cycle 6, a significantly higher proportion of
patients who received CC-486 achieved the primary
outcome of RBC transfusion independence lasting
≥56 days: 30.8% versus 11.1% (p=0.0002). The
investigators found that 28% of CC-486–treated
patients were transfusion independent for ≥84
days, compared with 5.6% of placebo-treated
patients (p<0.001).
Platelet transfusion independence rates were
similar between the CC-486 and placebo groups,
although the median duration of transfusion independence
was numerically longer among patients
treated with CC-486 (12.1 vs. 4.4 months).
Improvement in hemoglobin response was
greater in the CC-486 arm than the placebo arm,
with more patients experiencing a ≥1.5 g/dL hemoglobin
increase from baseline (p<0.0001). Mean
hemoglobin levels in the treatment arm increased
by approximately 2 g/dL from baseline to cycle 6.
Dr. Garcia-Manero pointed out that platelet counts
increased by an average of 38×10 9 /L by cycle 3 in
the active therapy group, and the improvements
in hemoglobin and platelet counts were sustained
during therapy. However, changes in hemoglobin
and platelets were considered negligible in the
placebo group.
In the safety analysis, the researchers noted that
approximately 30% of patients in the CC-486 group
and 28% in the placebo group discontinued treatment
because of AEs, the most common of which
were grades 1 and 2 gastrointestinal events. The
investigators reported that 90% of patients in the
CC-486 arm and 73% of patients in the placebo arm
experienced a grade 3/4 AE. Treatment-related AEs
occurred more frequently with CC-486, particularly
during cycles 1 and 2, Dr. Garcia-Manero noted.
The overall mortality rate was similar for
both arms, and median survival was similar (17.3
vs. 16.7 months, respectively; p=0.88). However,
more deaths occurred in patients treated with
CC-486 (n=16) than with placebo (n=6) between
days 1 and 56. Most deaths were associated with
infection. This resulted in early termination of the
study at the recommendation of the independent
DSMC. ●
The authors report relationships with Celgene,
the manufacturer of CC-486.
Reference
Garcia-Manero G, Santini V, Almeida A, et al. A phase III placebo-controlled trial of
CC-486 in patients with red blood cell transfusion-dependent (RBC-TD) anemia
and thrombocytopenia due to IPSS lower-risk myelodysplastic syndromes (LR-
MDS). Abstract S180. Presented as part of EHA25 Virtual, June 12, 2020.
28 ASH Clinical News July 2020 Bonus Mid-Year Edition