Adding
the
BCL2
inhibitor
venetoclax
(Venclexta)
to
chemoimmunotherapy
led
to
worse
outcomes
and
excess
mortality
in
patients
with
newly
diagnosed
double-hit
lymphoma,
phase
II
results
from
a
randomized
trial
showed.

Median
progression-free
survival
(PFS)
was
28.4
months
in
patients
who
received
dose-adjusted
etoposide,
prednisone,
vincristine,
cyclophosphamide,
doxorubicin,
and
rituximab
(DA-EPOCH-R)
versus
7.7
months
in
those
who
received
the
chemoimmunotherapy
regimen
plus
venetoclax
(HR
1.13,
95%
CI
0.53-2.37,

P=0.75),
reported
Jeremy
S.
Abramson,
MD,
of
the
Mass
General
Brigham
Cancer
Institute
in
Boston,
and
colleagues.

Median
overall
survival
has
not
been
reached
in
either
group,
and
the
24-month
overall
survival
estimates
were
72%
in
the
DA-EPOCH-R
group
compared
with
52%
in
the
group
that
received
added
venetoclax
(HR
2.49,
95%
CI
1.03-6.04,

P=0.038),
they
noted
in


Lancet
Haematology.

The
excess
mortality
observed
with
added
venetoclax
—
six
deaths
versus
one
death
in
the
DA-EPOCH-R
group
—
prompted
early
closure
of
the
trial.

The
worse
outcomes
were
primarily
due
to
increased
hematologic
toxic
effects
and
infections,
Abramson
and
colleagues
wrote.
“Venetoclax
clearly
enhances
the
toxicity
of
DA-EPOCH-R,
and
so
this
combination
is
not
recommended.”

They
pointed
out
that
the
results
in
the
DA-EPOCH-R
group
“demonstrate
durable
remissions
in
a
substantial
proportion
of
patients
and
provide
a
valuable
benchmark
for
future
studies.”

Double-hit
lymphoma,
defined
as
a
high-grade
B-cell
lymphoma
with
rearrangements
of

MYC
and

BCL2
and/or

BCL6,
accounts
for
about
5%
of
newly
diagnosed
cases
of
diffuse
large
B-cell
lymphoma
(DLBCL).
It
is
highly
aggressive
and
is
associated
with
poor
outcomes
after
standard
chemoimmunotherapy.

In
previous
studies,
intensive
treatment
approaches
with
regimens
such
as
DA-EPOCH-R

have
shown
promise,
and
it
has
become
a
preferred
treatment
option.
However,
PFS
is
still
inferior
to
expected
outcomes
for
patients
with
DLBCL
not
otherwise
specified,
“indicating
a
considerable
need
for
improvement,”
Abramson
and
team
noted.

Venetoclax
has
previously

demonstrated
potential
benefit
in
patients
with
DLBCL
when
combined
with
R-CHOP
(rituximab
plus
cyclophosphamide,
doxorubicin,
vincristine,
and
prednisone),
including
patients
demonstrating
BCL2
protein
overexpression
by
immunohistochemistry.

This
cohort
of
the
open-label
ALLIANCE
A051701
study
included
73
patients
with
newly
diagnosed
double-hit
lymphoma
and
an
Eastern
Cooperative
Oncology
Group
performance
status
score
of
0-2
who
were
recruited
from
41
hospitals
and
outpatient
clinics
in
the
U.S.
Between
October
2019
and
September
2020,
they
were
randomly
assigned
to
receive
DA-EPOCH-R
alone
or
DA-EPOCH-R
plus
venetoclax.

Median
age
was
65,
55%
were
men,
and
89%
were
white.
Most
patients
(89%)
had
double-hit
lymphoma
with

MYC
and

BCL2
rearrangements,
with
or
without

BCL6
rearrangement,
and
the
remaining
patients
had
rearrangements
of

MYC
and

BCL6
without

BCL2
translocation,
but
with
BCL2
protein
expression.
Median
follow-up
was
34.7
months.

Deaths
on
treatment
occurred
in
one
patient
in
the
DA-EPOCH-R
group,
due
to
dyspnea,
which
was
possibly
related
to
treatment,
and
six
patients
in
the
DA-EPOCH-R/venetoclax
group:
four
due
to
sepsis
(three
at
least
possibly
related
and
one
unrelated)
and
two
due
to
cardiac
arrest
(at
least
possibly
related).

Four
additional
patients
in
the
DA-EPOCH-R/venetoclax
group
had
deaths
reported
as
late
adverse
events
(lung
infection
with
unspecified
organism,
COVID-19,
septic
shock,
hypoxia)
compared
with
one
additional
patient
in
the
DA-EPOCH-R
group
(sepsis).

The
most
common
grade
3-4
non-hematologic
adverse
event
was
febrile
neutropenia,
occurring
in
43%
of
patients
in
the
DA-EPOCH-R/venetoclax
group
and
37%
of
those
in
the
DA-EPOCH-R
group.

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