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PAPER SPOTLIGHT
A Pediatric Regimen Is Effective
for Adolescents and Young Adults
With ALL
Adolescents and young adults
(AYAs) with newly diagnosed
acute lymphocytic leukemia (ALL)
who received a pediatric-inspired
regimen had better survival
outcomes than historical controls,
according to results from the pro-
spective CALGB 10403 study. The
findings, which were published in
Blood, suggest that AYA patients
may benefit from being treated
like “old children” rather than
“young adults.”
“Given the improvement in
survival compared with historical
CALGB controls and other recently
published studies from both the
U.S. and European cooperative
groups, we believe that an inten-
sified pediatric regimen should
be the basis for future trials de-
signed to further improve survival
rates for young adults with ALL,”
lead author Wendy Stock, MD,
from the University of Chicago
Comprehensive Cancer Center,
told ASH Clinical News.
The CALGB 10403 study
was a multicenter trial involv-
ing more than 70 participating
institutions throughout the
U.S. Between November 2002
and September 2012, 318 AYA
patients (age range = 17-39
years) with newly diagnosed B-
or T-precursor ALL were enrolled.
All participants had an Eastern
Cooperative Oncology Group
performance status of ≤2 and no
prior treatment for ALL (except
emergency therapy with corti-
costeroids or hydroxyurea for
TABLE.
hyperleukocytosis, superior vena
cava syndrome, or renal failure
associated with leukemic infil-
tration of the kidneys). Patients
with Philadelphia chromosome
(Ph)–positive ALL were excluded.
A total of 295 patients were
eligible for treatment and evalu-
able for response. Median age
among this group was 24 years
(range = 17-39). Treatment fol-
lowed the CALGB 10403 protocol
and consisted of induction, con-
solidation, interim maintenance,
delayed intensification, and
long-term maintenance therapy
with a vincristine, daunorubicin,
pegaspargase, and prednisone-
based approach.
Approximately 89 percent
of patients (n=263) achieved a
complete bone marrow response
by either the end of induction or
following the extension of induc-
tion therapy. Allogeneic hemato-
poietic cell transplantation was
performed in 20 patients who
achieved remission.
At a median follow-up of 64
months (range = 0.4-109.5), 64
percent of patients (n=190) were
alive. The median overall sur-
vival (OS) was not reached and
the three-year OS rate was 73
percent. This compared favor-
ably with historical controls of
patients aged 16 to 29 years with
B- or T-precursor ALL, in which
median OS was estimated to be
61 months (range = 39-89) and
the three-year OS rate was 58
percent (p values not reported).
Survival Outcomes
CALGB 10403
Overall survival, months (range)
3-Year overall survival (range) 73% (68-78%)
Event-free survival, months (range) 78.1 (41.8-NE)
3-Year event-free survival (range) 59% (54-65%)
Disease-free survival, months (range) 81.7 (58.4-NE)
3-Year disease-free survival (range) 66% (60-72%)
NE = not estimable
22
ASH Clinical News
NE
See the TABLE for other sur-
vival endpoints.
Ninety patients had a disease
relapse during or after therapy;
median post-relapse survival was
10 months (range = 7.0-14) and
the three-year survival rate was
23 percent.
The authors also conducted a
multivariable analysis to deter-
mine which pre-treatment pa-
tient and disease characteristics
(including age, sex, body mass
index, white blood cell count, and
cytogenetics) predicted survival
outcomes.
The only factors predictive of
a survival outcome were obesity
and aberrant CRLF2 expression,
which were both associated with
worse disease-free survival (DFS):
• obesity (hazard ratio [HR] =
1.82; p=0.04)
• Ph-like signature/CRLF2
expression (HR=2.84;
p<0.001)
In addition, among the 80 pa-
tients who had minimal residual
disease (MRD) measurements
available, MRD-negativity was
associated with improved three-
year DFS, compared with patients
with detectable MRD (85% vs.
54%; p=0.001).
The authors reported eight
treatment-related deaths during
the study, for a treatment-related
mortality rate of 3 percent. “This
was low and similar to those
reported in pediatric
trials of ALL,” they
noted. However,
“there was a higher
Historical Controls
incidence of he-
61 (39-89)
patic and thrombotic
58% (52-64%)
complications during
30 (22-38)
induction therapy
--
compared with what
has previously been
34 (28-50)
reported in younger
48% (41-55%)
patients with ALL.”
The most common grade ≥3
adverse events (reported in >10%
of patients) during the induction
phase included:
• hypofibrinogenemia (42%)
• hyperglycemia (31%)
• elevated transaminases (28%)
• febrile neutropenia (22%)
• infection (19%)
• elevated bilirubin (18%)
“While the regimen was safe …
certain chemotherapy-related
toxicities remain a challenge,” Dr.
Stock said, particularly in obese
patients with a body mass index
of >40, where survival rates were
significantly worse than in other
patients. “As we move forward in
the next U.S. intergroup study for
B-lineage ALL, our goal is to fur-
ther improve event-free survival
(EFS) by testing the addition of
the new immune-conjugate, ino-
tuzumab ozogamicin, to enhance
early eradication of MRD and to
evaluate its impact on Ph-like
ALL.” To address improvements
in EFS, Dr. Stock referenced the
A041501 trial, which is now enroll-
ing patients.
Because this study included
only patients up to age 40 years,
the findings may be limited in
generalizability across the older
patient population. However, the
researchers report that such an
intensive pediatric regimen may
increase the rate of toxicities in
older patients, which may result
in compliance difficulties.
“A large challenge [in future
research] will be to evaluate new
agents that might further improve
survival for our patients with
T-ALL, particularly for those high-
risk patients with early T-precursor
ALL,” Dr. Stock concluded.
The authors report no relevant
relationships; the trial was support-
ed in part by Leadiant Biosciences.
REFERENCE
Stock W, Luger SM, Advani AS, et al. A pediatric treatment
regimen for older adolescents and young adults with
acute lymphoblastic leukemia: results of CALGB 10403
(Alliance). Blood. 2019 January 19. [Epub ahead of print]
February 2019