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PAPER SPOTLIGHT
CD19-Directed CAR T-Cell
Therapy Associated With
High Rates of MRD
Negativity in Young
Patients with ALL
Though CD19-directed
chimeric antigen recep-
tor (CAR) T-cell therapies
have shown great promise
for the treatment of he-
matologic malignancies,
the possibility of routinely
bringing these therapies
into practice is hampered
by difficulties in manufac-
turing CAR T-cell products,
the heterogeneity of
anti-tumor responses, and
the potential for severe
treatment-related
toxicities.
According to results of
a phase I/II trial published
in Blood, young patients
treated with CD19 CAR T-
cell therapy at a maximum
tolerated dose (MTD) of
1x10 6 cell/kg achieved high
rates of minimal residual
disease (MRD)-negative
complete remission
(CR). The products were
engineered with a defined
CD4/CD8 T cell ratio, a
uniform level of CAR
expression, and a less dif-
ferentiated phenotype – a
process associated with a
high manufacturing suc-
cess rate.
“This study reinforces
that a high rate of remis-
sion can be obtained
with CD19-directed CAR
therapy,” lead author
Rebecca A. Gardner, MD,
from the Ben Towne Center
for Childhood Cancer
Research at the Seattle
Children’s Research
Institute, told ASH Clinical
News. “Additionally, this
manufacturing platform
has a very high feasibility
rate in deriving CAR T-cell
16
ASH Clinical News
products in heavily treated
patients.”
The study included 45
children and young adults
(median age = 12.3 years;
range = 1.3-25.4 years)
with relapsed/refractory
CD19-positive B-lineage
acute lymphocytic leuke-
mia (ALL). The researchers
included patients who
were between the ages
of 1 and 27 years, weighed
≥10 kg, had a life expec-
tancy of ≥8 weeks, had ad-
equate organ function, and
had an absolute lymphocyte
count of ≥100 cells/μL.
Most patients (62%;
n=28) had previously
undergone hematopoietic
cell transplantation (HCT),
and had confirmed CD19-
positive leukemia recur-
rence (defined as ≥0.01%
disease), no active graft-
versus-host disease, and
no immunosuppressive
therapy for ≥4 weeks prior
to the study. Patients
who had not undergone
HCT were required to have
second or later marrow
relapse, with or without
extramedullary disease.
Patients with significant
neurologic deterioration.
Seven patients had
previously received CD19-
directed therapy, including
blinatumomab (n=6) and
second-generation CD19-
specific CAR T cells (n=1).
All patients had suc-
cessful manufacturing
of a clinical CAR T-cell
product; 33 products were
manufactured from fresh
apheresis material, and 12
from cryopreserved CD4
and CD8 T-cell
subsets. How-
ever, two patients
were not infused
with CAR T cells
because their
products did not meet the
study’s manufacturing
specifications.
Detectable engraft-
ment and expansion of
CAR T cells was observed
in 98 percent of treated
patients (n=42/43), and B-
cell aplasia (BCA; a marker
of T-cell persistence)
occurred in 93 percent of
patients (n=40).
All patients pretreated
with fludarabine and
cyclophosphamide to
achieve lymphodepletion
(n=14) achieved uniform
engraftment of functional
CAR T cells (defined as
CAR T cells in the blood
and subsequent develop-
ment of BCA and MRD-
negative remission). The
median time to peak
engraftment in peripheral
blood was 10 days (range =
7-18 days).
After a median follow-
up of 9.6 months (range =
2-28 months), the esti-
mated 12-month event-
free survival was 50.8
percent (95% CI 36.9-69.9)
and the overall survival
was 69.5 percent (95% CI
55.8-86.5). All remissions
occurred by day 21.
Disease burden, relapsed/
refractory status, prior
HCT, and cytogenetic sta-
tus did not affect MRD-
negative CR, according to
the authors.
Eighteen of the 40
patients who achieved
MRD-negative CR
relapsed. Seven of those
patients also had loss of
cell surface detection of
CD19; among the other 11
patients, median time from
T-cell infusion to relapse
was 5.98 months (range =
1.25-14 months), with a me-
dian time from loss of BCA
to relapse of 3.7 months
(range = 0-11 months).
Twenty-nine patients
who achieved MRD-
negative CR did not go
on to receive consolida-
tive HCT and 13 were still
in continuous CR after a
median follow-up of 12.2
months (range = 1.9-27.5
months). “A longer dura-
tion of post-remission
functional persistence of
CAR T cells, as inferred by
ongoing BCA, correlated
significantly with the
durability of remission,”
the authors noted.
Among the 40 com-
plete responders, loss of
functional CAR T cells was
associated with a greater
risk of CD19-positive
leukemic relapse (hazard
ratio [HR] = 34; 95% CI
2.1-552; p=0.01), whereas
the HR for all relapses, in-
cluding CD19-positive and
-negative, was 3.5 (95% CI
1.01-11.88; p=0.04).
The most common
adverse events were
cytokine release syndrome
(CRS; 93%; n=40/43)
and neurotoxicity (49%;
n=21/43). “A correlation
between disease burden
at the time of CAR T-cell
infusion and severity of
CRS was not observed
(p=0.56), nor with CD19
antigen load (p=0.13),” the
authors reported. Notably,
there were no cases of
cerebral edema, a safety
concern that has emerged
in trials of other CAR T-cell
therapies.
“These data estab-
lish the feasibility of this
advanced manufacturing
platform and support fur-
ther study of this highly
defined CD19 CAR T-cell
product,” the authors
concluded.
The study is limited by
its short follow-up period,
small patient numbers, and
non-comparative design.
Furthermore, “since this is
a phase I study, additional
data will be informative
from the phase II study to
better delineate potential
risk factors of toxicity and
relapse,” Dr. Gardner told
ASH Clinical News. The
researchers are conducting
a phase II study treat-
ing patients at the MTD
of 1x10 6 cell/kg following
fludarabine and cytarabine
lymphodepletion.
REFERENCE
Gardner RA, Finney O, Colleen Annesley C,
et al. Intent to treat leukemia remission by
CD19CAR T cells of defined formulation and
dose in children and young adults. Blood.
2017 April 13. [Epub ahead of print]
July 2017