CLINICAL NEWS
Transgene Levels Not Sufficient
for Treatment Decisions in CAR
T-Cell–Treated Patients
An analysis of three clinical trials of tisagenlecleucel found that levels of
chimeric antigen receptor (CAR) transgene (or the gene that is artificially
introduced into a patient’s genome) are highly variable in patients with
relapsed/refractory acute lymphocytic leukemia (ALL) and diffuse large
B-cell lymphoma (DLBCL), suggesting that transgene levels are not a
reliable biomarker for guiding clinical decisions in these patients.
Rakesh Awasthi, PhD, senior scientist at Novartis, which manufac-
tures tisagenlecleucel, presented these findings at the 2019 American
Association for Cancer Research Annual Meeting.
“With the emerging data, it is important to improve our current under-
standing regarding the significance of in vivo expansion and persistence of
CAR T cells as it relates to response,” Dr. Awasthi told ASH Clinical News.
“The transgene levels associated with maximal expansion and at later time
points showed high variability among both responders and nonresponders
[with ALL and DLBCL]. Based on the data presented, a definitive cut point
predicting response could not be ascertained.”
Of the three included trials, two studied tisagenlecleucel in pediatric
or young adult patients with ALL: ELIANA, which enrolled 75 patients,
and ENSIGN, which enrolled 29 patients. The JULIET trial enrolled 93
adult patients with DLBCL. All participants received a single infusion of
tisagenlecleucel.
To investigate the relationship between transgene persistence and
clinical response, the researchers examined CAR transgene levels with
quantitative polymerase chain reaction.
They found that responders and nonresponders in both patient cohorts
had detectable CAR transgene levels, with a median time to maximal
transgene level of nine to 10 days (range not provided). While there was
a similar geometric mean maximal expansion between responders and
nonresponders with DLBCL, there was a 1.7-fold difference in patients
with ALL (p values not reported).
The investigators observed high interindividual variability in transgene
levels in both disease cohorts. CAR T-cell expansion levels were lower
in the blood of patients with DLBCL, which the researchers suggest may
be “due to partitioning of functional CAR T cells to target sites including
lymph nodes.”
Compared with nonresponders, responders in both disease cohorts
had longer median time to their last quantifiable transgene level and lon-
ger transgene half-life – two markers of T-cell persistence. Despite this
observation, “in some cases, transgene levels were not detectable at later
timepoints in patients with continued response,” Dr. Awasthi noted. He
added that a smaller proportion of patients still demonstrated a favor-
able clinical response following a reduction in levels to below the level of
quantification.
“We have shown that pediatric patients with ALL can maintain
durable responses despite loss of transgene,” Dr. Awasthi commented.
“In certain patients, one potential reason for this observation is that the
initial expansion and persistence sufficiently eradicated the tumor.”
He added that, in the DLBCL cohort, the expansion was similar be-
tween responders and nonresponders according to data from peripheral
blood samples. “In addition, quantifiable transgene levels were observed
in some patients with DLBCL at the time of relapse. These findings
underscore the importance of characterizing and understanding traffick-
ing of CAR transgene to the tumor site by obtaining post-treatment and
progression biopsies,” he concluded.
The study’s implications are limited by the small number of patients
enrolled in these trials. It also is unknown whether these results will be
generalizable to other approved or investigational CAR T-cell therapies.
The authors report relationships with Novartis, which sponsored both
trials included in this analysis.
Umbralisib Confers Durable
Response, Tumor Reductions in
Patients With Relapsed/Refractory
Marginal Zone Lymphoma
While rituximab-based treatment has im-
proved outcomes for patients with marginal
zone lymphoma (MZL), most patients
eventually have a disease relapse. According
to results from an ongoing study presented
at the 2019 American Association for Can-
cer Research Annual Meeting, umbralisib
monotherapy led to responses in more than
half of patients with relapsed/refractory
MZL. The responses also appeared to be
durable, reported lead author Nathan H.
Fowler, MD, of the MD Anderson Cancer
Center in Houston.
“Umbralisib is a small-molecule in-
hibitor that targets PI3K-delta, which is a
component of a signaling pathway that has
a key role in promoting the survival and
expansion of many types of cells,” said Dr.
Fowler. “[Our findings] suggest that this
oral targeted therapeutic has significant
activity against relapsed/refractory MZL
and offers hope for patients.”
Eligible participants had histologically
confirmed MZL, an Eastern Cooperative
Oncology Group performance score ≤2,
and previously received at least one prior
therapy (including at least one CD20
monoclonal antibody–containing regimen).
Patients were treated with umbralisib 800
mg daily until either disease progression
or unacceptable toxicity.
As of October 20, 2018 (data cutoff),
69 patients (median age = 67 years; range
= 34-81 years) were enrolled in the trial.
Dr. Fowler reported data from 38 patients
who had at least six months of follow-up.
Of these, patients had extranodal (n=23),
nodal (n=8), or splenic (n=7) disease.
Participants had received a median of
two prior systemic therapies (range = 1-5
therapies); seven patients (18%) received
single-agent rituximab and 26 (68%)
received at least one CD20 monoclonal
antibody–containing regimen.
During a median follow-up of 9.6
months, the overall response rate was 55%,
including four complete responses and
17 partial responses. Another 11 patients
(29%) achieved stable disease.
Overall, the median time to an initial
response to therapy was 2.7 months
(range not reported). The median dura-
tion of response was not reached at
data cutoff (range = 8.4 months to not
reached), and the 12-month progression-
free survival rate was 71%.
The authors also reported that 91% of
patients who had at least one post-base-
line assessment experienced reductions in
tumor volume.
The most common adverse events (AEs;
reported in ≥20% of patients) included:
• diarrhea (45%)
• nausea (29%)
• fatigue (26%)
• headache (26%)
• cough (24%)
• decreased appetite (21%)
The most frequently reported grade 3/4
AEs included neutropenia (8%), febrile
neutropenia (5%), and diarrhea (5%). As of
data cutoff, 16 patients discontinued ther-
apy due to progressive disease (n=7; 18%),
AEs (n=3; 8%), patient decision (n=3; 8%),
or physician decision (n=3; 8%).
The observed AEs “are to be expected
with this class of drugs,” and did not ap-
pear to worsen with prolonged exposure
to the study drug, said Dr. Fowler.
The findings are limited by the small
patient cohort, short duration of follow-up,
and lack of a comparator arm. Dr. Fowler
noted that the researchers are continuing
to follow patients to establish the long-term
activity and side effects of umbralisib. ●
The authors report relationships with TG
Therapeutics, which sponsored the trial.
REFERENCE
Fowler NH, Samaniego F, Jurczak W, et al. Umbralisib monotherapy
demonstrates efficacy and safety in patients with relapsed/refractory
marginal zone lymphoma: a multicenter, open-label, registration directed
phase II study. Abstract #CT132. Presented at the American Association
for Cancer Research Annual Meeting, April 1, 2019; Atlanta, GA.
REFERENCE
Awasthi R, Mueller KT, Yanik GA, et al. Evaluation of in vivo chimeric antigen receptor (CAR) transgene levels in patients
(pts) treated with tisagenlecleucel. Abstract #CT237. Presented at the American Association for Cancer Research Annual
Meeting, April 2, 2019; Atlanta, GA.
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