CLINICAL NEWS
PERSPECTIVES
This trial is the first to demonstrate the effectiveness of weekly selinexor when given in
combination with other anti-myeloma drugs. Half the patients required a dose reduc-
tion of selinexor, most often due to cytopenias, nausea, or fatigue. At the recommended
phase II dose, 73 percent suffered grade 1/2 nausea and 62 percent grade 1/2 fatigue,
despite protocol-mandated antiemetics. In comparison, when adjusted for grade, about
half as many patients had similar side effects in trials of carfilzomib, lenalidomide, and
dexamethasone or daratumumab, lenalidomide, and dexamethasone – although both
lenalidomide-related combinations caused more diarrhea.
In the phase III BOSTON trial, selinexor has shown similar responses in diffuse
large B-cell lymphoma It crosses the blood-brain barrier, potentially allowing it to
target glial tumors, and targeting this pathway may have a bright future.
Craig Hofmeister, MD, MPH
Winship Cancer Institute
Emory University School of Medicine
Atlanta, GA
Enasidenib Induces Molecular Remissions in IDH2-Mutated, Relapsed/Refractory AML
A first-in-human trial of patients with re-
lapsed and/or refractory, IDH2-mutated
acute myeloid leukemia (AML) found
that the IDH2 inhibitor enasidenib was
an effective salvage therapy, inducing
responses in approximately 40 percent
of study participants. In a recent article
published in Blood, the authors provided
updated results from the study, looking
specifically at molecular remissions.
“In our study, approximately 30
percent of patients with a best response
of stable disease at 90 days (after three
cycles of therapy) went on to have a
response, suggesting that in the absence
of clear evidence of progressive disease,
patients who have stable disease on day
90 should continue on therapy, as they
may achieve a response,” lead author
Eytan M. Stein, MD, of the Memorial
Sloan Kettering Cancer Center in New
York, told ASH Clinical News. “Ena-
sidenib also is able to clear the IDH2
mutant clone in a subset of patients who
enter a complete remission.”
The phase I/II study evaluated
enasidenib (administered in continuous
28-day cycles) in adults with IDH2-
mutated AML that had relapsed after
allogeneic hematopoietic cell trans-
plantation (alloHCT), was in second or
later relapse, was refractory to initial
induction or reinduction treatment, or
had relapsed within one year of initial
treatment.
To monitor mutation clearance and
hematologic response, the investigators
collected bone marrow biopsies and
peripheral blood samples at screening,
on day 1 of cycle 2, and then every 28
days for a total of 12 months, followed by
every 56 days thereafter.
A total of 280 patients with relapsed/
refractory AML from 21 sites were
enrolled, all of whom received a median
of five cycles of enasidenib (range = 1-38
cycles). The authors also reported results
for a subgroup of patients who received
enasidenib 100 mg/day (n=214; 76.2% of
entire study population). Median age in
this group was 68 years (range = 19-100
years), and 48 (22.4%) had received at
least three prior therapies for AML.
ASHClinicalNews.org
“Safety outcomes for all patients were
consistent with those reported previ-
ously,” the investigators reported. The
most common any-grade adverse events
(AEs) included:
• indirect hyperbilirubinemia (40.3%)
• nausea (28%)
• decreased appetite (17.7%)
The most commonly reported grade 3-4
treatment-emergent AEs included:
• hyperbilirubinemia (10.4%)
• IDH differentiation syndrome
(IDH-DS; 6.4%)
• anemia (5.5%)
The development of IDH-DS is an AE
unique to treatment with enasidenib, Dr.
Stein explained, advising that clinicians
be aware of this risk. “As opposed to
reinduction chemotherapy, enasidenib
is a differentiation agent and leads to
maturation of malignant myeloblasts into
neutrophils,” he said. “Failure to recognize
and promptly administer corticosteroids
for differentiation syndrome can lead
to respiratory failure from pulmonary
edema.”
At a median follow-up of 7.8 months
(range not reported), response rates were
similar between the enasidenib 100 mg/day
cohort and the entire study population.
The overall response rate (defined as
complete remission [CR], CR with
incomplete count recovery [CRi/CRp],
and partial remission [PR]) was 33.2
percent in the 100 mg/day cohort and
33.9 percent across all dosing cohorts.
Approximately 19 percent of patients in
each group experienced a CR. Response
rates did not appear to differ based on
relapsed or refractory disease status, the
authors reported.
Survival outcomes also were similar
in the 100-mg/day and all dosing groups:
The median overall survival (OS) was
8.8 months (ranges = 7.7-9.6 months
and 7.8-9.9 months, respectively), and
median event-free survival (EFS) was 4.7
months (range = 3.7-5.6 months) and
4.6 months (range = 3.7-5.6 months),
respectively. See more response and
survival data in the TABLE.
Achieving a CR was associated with
longer median OS, compared with those
with less than a CR or no response (22.9
months vs. 10.6 months and 5.6 months;
p value not reported), respectively. In
addition, the median OS was longer in
patients who had received one versus
two or three previous AML treatments
prior to enrollment (11.8 months vs. 7.8
months and 7.0 months, respectively;
p=0.001).
Among the 101 patients in the 100
mg/day group who had variant allele fre-
quency (VAF) data available, 12 (11.9%)
achieved mutant-IDH2 molecular remis-
sion (defined as IDH2 VAF <0.02%-0.04%
at one or more time point), and achiev-
ing this endpoint was significantly
associated with response to treatment,
compared with no molecular remission
(p=0.0003).
Attaining molecular remission
was also associated with “a significant
survival advantage,” the investigators
wrote (median OS = 22.9 months vs. 8.8
months, respectively; p=0.0153).
TABLE.
“Enasidenib served as a bridge to
transplant for several patients with re-
lapsed or refractory disease,” the authors
added, with 19 patients in the 100 mg/day
group who achieved a CR subsequently
undergoing alloHCT.
Enasidenib also led to transfusion
independence. Among the patients
in the 100-mg/day group who were
transfusion-dependent at baseline, 43.1
percent (n=66/153) achieved red blood
cell transfusion independence and 40.2
percent (n=53/132) achieved platelet
transfusion independence.
Limitations of the study include
the relatively small number of patients
enrolled, as well as the lack of a placebo
and/or active treatment comparator arm.
Dr. Stein added that enasidenib is now
being evaluated in a randomized, phase
III study of older patients with late-stage,
IDH2-mutated, relapsed/refractory
AML, in which it will be compared with
conventional care regimens.
The study authors report financial re-
lationships with Agios and Celgene, which
cosponsored the trial.
REFERENCE
Stein EM, DiNardo CD, Fathi AT, et al. Molecular remission and response
patterns in patients with mutant-IDH2 acute myeloid leukemia treated
with enasidenib. 2018 December 3. [Epub ahead of print]
Investigator-Reported Efficacy Outcomes
Enasidenib 100 mg/day
(n=214) All Doses
(n=280)
CR 42 (19.6%) 53 (18.9%)
CRi/CRp 20 (9.3%) 25 (8.9%)
Best response
Partial remission 9 (4.2%) 17 (6.1%)
Morphologic leukemia-free state 12 (5.6%) 16 (5.7%)
98 (45.8%) 122 (43.6%)
19 (8.9%) 26 (9.3%)
Stable disease
Progressive disease
Not evaluable
Time to first response, months (range)
3 (1.4%) 4 (1.4%)
1.9 (0.5-9.4) 1.9 (0.5-9.4)
Duration of response, months (range) 5.6 (3.8-7.4) 5.6 (4.6-6.5)
Time to best response, months (range) 3.7 (0.7-14.7) 3.8 (0.5-14.7)
Overall survival, months (range) 8.8 (7.7-9.6) 8.8 (7.8-9.9)
Event-free survival, months (range) 4.7 (3.7-5.6) 4.6 (3.7-5.6)
CR = complete remission; CRi/CRp = complete remission with incomplete count recovery
ASH Clinical News
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