Literature Scan
New and noteworthy research from the
medical literature landscape
JULIET Analysis Finds Durable Responses
With Tisagenlecleucel in DLBCL
Half of patients with relapsed or refractory
diffuse large B-cell lymphoma (DLBCL)
responded to tisagenlecleucel, and ap-
proximately two-thirds of responders are
expected to remain progression-free at one
year, according to updated results from the
phase IIa JULIET trial. The findings were
published in the New England Journal of
Medicine.
“The high and durable response rates
are promising … but the potential long-
term toxic effects require further analysis,”
lead author Stephen Schuster, MD, from
the Perelman School of Medicine at the
University of Pennsylvania, and colleagues
wrote.
Tisagenlecleucel, a chimeric antigen
receptor (CAR) T-cell therapy that targets
and eradicates CD19-expressing B cells,
was approved by the U.S. Food and Drug
Administration in May 2018 for the treat-
ment of relapsed or refractory DLBCL based
on earlier results from the JULIET trial.
With this update, the investigators
evaluated response rates and response
duration in 165 adults with DLBCL who
were enrolled from 27 sites in 10 countries.
Ultimately, 111 patients (median age = 56
years; range = 22-76 years) received CAR
T-cell infusion; 30 percent of enrolled
patients discontinued the study without
receiving an infusion, mostly as a result of
disease progression and death.
Participants had previously been treated
with at least two lines of therapy (including
rituximab and an anthracycline) and had
either a relapse after or were ineligible for
autologous hematopoietic cell transplanta-
tion (HCT). JULIET also included patients
who had DLBCL that had transformed
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from follicular lymphoma or who had
double- or triple-hit lymphoma. Patients
who had previously received CD19-directed
therapy or had received an allogeneic HCT
were excluded from the trial.
The study protocol allowed for bridging
therapy between leukapheresis and CAR
T-cell manufacturing and infusion. Ninety-
two percent of patients received bridging
therapy with rituximab, gemcitabine,
dexamethasone, and other agents.
Prior to infusion of tisagenlecleucel,
patients also received one cycle of lympho-
depleting chemotherapy with either
fludarabine and cyclophosphamide or
bendamustine.
The median time from enrollment to
infusion was 54 days (range not provided),
and patients were infused with a single
dose of tisagenlecleucel (median = 3.0×10 8
cells; range = 0.1-6.0×10 8 cells). The CAR
T-cell therapy was centrally manufactured
via cryopreserved apheresis and a global
supply chain.
All 111 patients who received a CAR
T-cell infusion were included in the safety
analysis; the efficacy analysis included the
93 patients who had follow-up of at least
three months.
Over a median follow-up of 14 months
(range = 0.1-26 months), the best overall
response rate (ORR) was 52 percent;
the majority of responses were complete
responses (CRs; 40%) and the remain-
ing were partial responses (PRs; 12%).
Response rates were consistent across
prognostic subgroups, the researchers
noted, including age, previous response
status, and molecular subtype.
At three months, the ORR was 38 per-
cent, and the CR rate was 32 percent. At six
months, ORRs and CR rates were 33 per-
cent and 29 percent, respectively, suggesting
that most early responses were durable.
Among the 37 patients who had a CR,
four patients had stable disease and 12
had a PR at one month after CAR T-cell
TABLE.
ASH Clinical News
REFERENCE
Schuster SJ, Bishop MR, Tam CS, et al. Tisagenlecleucel in adult relapsed or
refractory diffuse large B-cell lymphoma. N Engl J Med. 2019;380:45-56.
Adverse Events of Interest
Incidence of Adverse Events
Any Grade
Grade 3/4
Cytokine release syndrome 64 (58%) 23 (22%)
Infection 38 (34%) 22 (20%)
Cytopenia not resolved by day 28 49 (44%) 36 (32%)
Neurologic event 23 (21%) 13 (12%)
Febrile neutropenia 17 (15%) 16 (15%)
1 (1%) 1 (1%)
Tumor lysis syndrome
24
infusion, which improved to a CR within
a median of two months (range = 1-17
months), the authors noted. Also, more
than half of patients with a PR converted to
a CR (n=13/24; 54%). According to these
observations, the authors predicted that
79 percent of patients who had a CR and
65 percent of all responders were likely to
remain relapse-free one year after infusion.
At the time of data cutoff, the median
response duration had not been reached
(range = 10 months to not reached). Sim-
ilarly, the median progression-free sur-
vival (PFS) had not been reached, yet the
estimated 12-month PFS was 83 percent
among patients who responded at three
months. Achieving a CR increased the
probability of 12-month overall survival
(OS), the researchers added: The estimated
12-month OS rate was 49 percent among
all treated patients, but 90 percent among
those who achieved a CR.
The authors noted that the adverse
events (AEs) were similar to those experi-
enced with other CAR T-cell products. The
most common AEs included cytokine re-
lease syndrome (CRS) in 64 patients (58%);
23 patients (22%) had grade 3 or 4 CRS. See
TABLE for incidence of other AEs of interest.
Three participants died within 30 days
of tisagenlecleucel infusion; however, deaths
were not considered related to the study
drug or CRS. The investigators noted no
new deaths for reasons other than disease
progression since earlier reports from
JULIET.
Limitations of the study include its
small sample size, the sizable proportion of
patients who discontinued study participa-
tion, the lack of a control group, and the
open-label design.
The authors report relationships with
Novartis, which supported the study.
April 2019