CLINICAL NEWS
On Location 2018 ASH Annual Meeting
Predicting Response to Alvocidib in
Patients With Relapsed/Refractory AML
The CDK9 inhibitor alvocidib induced
a high rate of responses in patients with
relapsed or refractory acute myeloid
leukemia (AML) who had MCL1-
dependent disease, according to results
from the first stage of the phase II Zella
201 trial. These findings suggest that
MCL1 dependence is a valuable biomark-
er in this patient population, said lead
author Joshua Zeidner, MD, from the
University of North Carolina Lineberger
Comprehensive Cancer Center, during
his presentation at the 2018 ASH Annual
Meeting.
“By inhibiting CDK9, alvocidib
downregulates and inhibits MCL1 ex-
pression,” Dr. Zeidner explained. “MCL1
is a dominant pro-survival mechanism
that is upregulated in [patients with
AML].”
Based on previous research that
found that patients with AML and
MCL1 dependence ≥40 percent had an
increased sensitivity to alvocidib, the
authors hypothesized that alvocidib, fol-
lowed by cytarabine and mitoxantrone,
would be “preferentially active” in this
patient population.
The Zella 201 trial included adult
patients (age range = 18-65 years) with
AML that was refractory to induction
therapy or that was in first relapse with
a complete remission (CR) for less than
two years. Patients who had undergone
prior allogeneic hematopoietic cell trans-
plantation were included if the procedure
happened longer than two months before
enrollment and if there was no active
graft-versus-host disease.
A total of 170 patients were enrolled
and screened for MCL1 dependence
≥40 percent; 48 participants (28%) were
determined to have MCL1-dependent
disease and were treated with the follow-
ing regimen:
• alvocidib 30 mg/m 2 administered as
a 30-minute intravenous (IV) bolus,
followed by 60 mg/m 2 over 4 hours
on days 1-3
• cytarabine 667 mg/m 2 per day by
continuous IV infusion on days 6-8
• mitoxantrone 40 mg/m 2 IV on day
9 starting 12 hours after completing
cytarabine
Patients who responded to treatment
were permitted to receive up to three ad-
ditional cycles of the same regimen (with
or without mitoxantrone).
Dr. Zeidner shared results from the
first 23 evaluable patients. Per study pro-
tocol, stage 1 of the trial was determined
to be positive if at least 13 CRs were
38
ASH Clinical News
observed in this group; if this bench-
mark was met, stage 2 of the trial could
proceed.
The overall response rate (ORR)
was 61 percent, and 13 patients (57%)
achieved the primary endpoint (CR or
CR with incomplete recovery [CRi]).
One additional patient experienced a
partial remission.
CRs and CRis also were observed in
patients with high-risk disease character-
istics, defined as follows:
• refractory disease: 7 of 12 patients
(58%)
• early relapse: 4 of 7 patients (57%)
• late relapse: 2 of 4 patients (50%)
• unfavorable cytogenetics: 2 of 5
patients (40%)
Four of the first 23 enrolled patients died
early before response assessment (3 due
to sepsis, 1 due to mitral valve rupture),
Dr. Zeidner reported.
The median duration of response was
8.5 months (range = 2.1-15.9 months)
and the median overall survival was 11.2
months (range = 3.0-16.8 months).
The most common grade 3 non-
hematologic adverse events (AEs)
included diarrhea (24%) and tumor lysis
syndrome (TLS; 20%). TLS occurred
rapidly, within eight to 12 hours after
alvocidib administration.
TLS events observed in this popula-
tion were “only a biochemical phenom-
enon [and] not associated with clinical
decline,” Dr. Zeidner said, adding that
“we can manage the TLS, we just have to
vigorously monitor these patients.”
“The clinical activity rate compares
favorably to historical controls,” Dr.
Zeidner concluded, though the lack
of a comparator arm is a limitation of
this study. Based on the positive results
observed in stage 1, investigators are
moving forward to stage 2, which will
compare the alvocidib regimen with a
standard cytotoxic chemotherapy regi-
men in patients with relapsed/refractory
AML.
The authors report relationships with
Tolero Pharmaceuticals, which sponsored
this trial.
REFERENCE
Zeidner JF, Lin TL, Vigil CE, et al. Zella 201: a biomarker-guided phase
II study of alvocidib followed by cytarabine and mitoxantrone in MCL-1
dependent relapsed/refractory acute myeloid leukemia (AML). Abstract
#30. Presented at the 2018 ASH Annual Meeting, December 1, 2018;
San Diego, CA.
Mixed Results for
Immunotherapy Approaches in
Myelodysplastic Syndromes
complex karyotype and high-risk
genomic features, according to Dr.
Garcia-Manero.
In the HMA-failure group,
patients were assigned to receive
either nivolumab (3 mg/kg every 2
weeks) or ipilimumab (3 mg/kg
every 3 weeks). In the frontline
group, patients received a back-
bone of azacitidine (75 mg/m 2
for 5 days) plus nivolumab or
ipilimumab.
In the HMA-failure cohort, pa-
tients could receive azacitidine again
if they had no response to six cycles
of immune checkpoint inhibitors.
At a median follow-up of 20.1
months (range = 1-33 months),
the overall response rate (ORR)
appeared to be highest in the
nivolumab plus azacitidine com-
bination for previously untreated
patients and lowest for HMA-failure
patients who received single-agent
nivolumab ( TABLE ). Treatment of
this cohort was stopped early for a
lack of response.
In the frontline group, median
overall survival (OS) was not
reached in the ipilimumab plus
azacitidine group but was 11.8
months in the nivolumab plus
azacitidine group (ranges not
reported). In the HMA-failure
cohort, median OS was 8.5 months
with ipilimumab and 8.0 months
with nivolumab (ranges not
reported).
“These agents can be associated
with significant toxicities includ-
ing colitis and other inflamma-
tory processes that require steroid
Findings from trials evaluating new
treatment strategies for patients
with myelodysplastic syndromes
(MDS) produced mixed results:
Combining an immune check-
point inhibitor with azacitidine
was associated with high response
rates, although perhaps ones that
don’t differ much from azacitidine
monotherapy, while the PD-L1
inhibitor atezolizumab plus azaciti-
dine was associated with a high
early mortality rate.
Immune Checkpoint Inhibitors
With or Without Azacitidine
In the first trial, researchers found
that treatment with the immune
checkpoint inhibitors ipilimumab
or nivolumab, with or without the
hypomethylating agent (HMA)
azacitidine, showed clinical activity
– but distinct toxicity profiles – in
patients with previously treated
MDS or disease that failed to re-
spond to HMA treatment.
Lead author Guillermo Garcia-
Manero, MD, from the University
of Texas MD Anderson Cancer
Center, presented the findings from
this trial, which enrolled adults with
untreated MDS or with MDS that
did not respond to HMA treatment.
In the HMA-failure cohort, patients
had received HMA therapy within
four months of enrollment and no
other therapy after HMA exposure.
A total of 76 participants were
divided into frontline (n=41) and
HMA-failure groups (n=35). Patient
characteristics were balanced;
most patients had an abnormal or
Continued on page 40
Response Rates With Immune Checkpoint
Inhibitors
TABLE.
Frontline
HMA-Failure
Nivolumab
+ azacitidine
(n=20) Ipilimumab
+ azacitidine
(n=21) Nivolumab
(n=15) Ipilimumab
(n=20)
Overall response
rate 14 (70%) 13 (62%) 0 6 (30%)
Complete
response 8 (40%) 3 (14%) 0 0
Marrow complete
response (with
or without
hematologic
improvement) 5 (25%) 7 (33%) 0 4 (20%)
Hematologic
improvement 1 (5%) 3 (14%) 0 3 (15%)
Stable disease 0 1 (5%) 0 0
5 (25%) 5 (24%) 15 (100%) 13 (65%)
No response
HMA = hypomethylating agent
February 2019