FEATURE
Features
The Middle Ages:
Controversies in the
Treatment of Adolescents
and Young Adults With
Leukemia
Over the past few decades, survival
rates for pediatric patients with acute
lymphocytic leukemia (ALL) have
improved dramatically, with five-year
survival rates now often exceeding
90 percent and 10-year survival rates
exceeding 80 percent, according to a
review of Children’s Oncology Group
ALL trials between 1990 and 2005. 1
These improvements were seen re-
gardless of patient sex, age, ethnicity,
and immunophenotype.
These statistics pertain to patients
diagnosed in infancy through those
diagnosed at age 22, however, leaving
out a substantial portion of one of the
most challenging-to-treat segments of
the ALL population: adolescents and
young adults (AYAs).
Patients who fall into this age group
(typically defined as people aged 15 to
39 years) experience worse outcomes
than their pediatric counterparts
and have not seen similarly dramatic
increases in survival. 2 According to a
2009 study published in Blood, five- and
10-year survival rates for patients be-
tween the ages of 20 to 29 were just 44.8
percent and 38 percent, respectively. 3
The contrast between the two
groups’ survival outcomes has sparked
new efforts to figure out what makes
ALL in AYA patients distinct from ALL
in pediatric – and even adult – patients.
Research into the survival outcomes
of AYA patients has only highlighted
the group’s heterogeneity. Studies have
suggested that patients aged 15 to
39 years have better prognosis when
treated with a pediatric regimen rather
than an adult regimen, but survival
rates vary significantly based on where
they receive that treatment and a host of
other psychosocial factors.
“Depending on the center or the
site, the issue of where AYA patients
should be treated – and whether they
ASHClinicalNews.org
should receive a pediatric or adult
regimen – is still up for debate,” said
Anjali Advani, MD, director of the
inpatient leukemia unit and professor
of medicine in the Cleveland Clinic
Lerner College of Medicine.
ASH Clinical News spoke with Dr.
Advani and clinicians specializing in
the treatment of pediatric and AYA
patients with leukemia about what de-
fines this distinct patient group, who
should be treating them, and why the
issue continues to ignite controversy.
Who Are AYAs?
Age is only a number, and there are
many qualities that distinguish AYA
patients with leukemia from patients
at either end of the age spectrum –
and that affect their overall survival.
“Everything changes during the ado-
lescent and young adult years, compared
with childhood,” said Wendy Stock,
MD, the Anjuli Seth Nayak Professor in
Leukemia at the University of Chicago.
“That has to do with the biology of the
disease and, of course, with the biology
of the person with the disease.”
These factors all play a role in how
ALL affects patients’ lives. “Psycho-
logically, these people are very different
from children with leukemia and they
face different problems,” she added. Un-
til recently, there had been little research
focused on AYA patients, according to
Dr. Stock, making it difficult to draw any
conclusions about why ALL in this pa-
tient population traditionally responded
poorly to treatments, compared with
ALL in pediatric patients.
“[AYAs] have been under-
represented as an entity in clinical tri-
als. They are the patient group with the
lowest accrual for any kind of clinical
trial in cancer because there was virtu-
ally no focus on this age group in clini-
cal trials,” said Dr. Stock, who directs
the leukemia program at the University
of Chicago. Enrollment rates in NCI-
sponsored trials for people aged 15 to
22 years, for example, averaged about
22 percent, while rates among pediatric
and adult patients averaged 38 percent
and 27 percent. 4
“These patients often were just
split in terms of where they would
seek care, without little information
about why,” Dr. Stock said, but recent-
ly, research has given hematologists/
oncologists more insight into how
ALL manifests in this patient group.
Certain factors of leukemia in the
AYA population confer a worse prog-
nosis than is seen within pediatric
patients: For example, the presence of
the Philadelphia chromosome (Ph)
increases with age, and more AYA pa-
tients than pediatric patients have Ph-
positive disease – a genetic signature
that often signals that a patient will
not respond as well to treatment. 5
According to Dr. Advani, Ph-
positive B-cell ALL occurs in ap-
proximately 20 to 30 percent of the
AYA population and is seen much less
frequently in pediatric patients. “Now,
there are clinical trials ongoing to spe-
cifically treat patients with this type of
disease, which is important, because
results from those trials could give us
insights about a feature that is unique
to this population,” she said.
In addition, pediatric patients un-
der the age of 10 are more likely than
older AYA patients to display favor-
able cytogenic features, such as having
hyperdiploidy in leukemic blasts,
favorable trisomies of chromosomes 4,
10 and 17, or the TEL/AML translo-
cation. 6 AYA patients also are more
likely than children to present with
more high-risk factors, including the
T-cell phenotype or the BCR-ABL–like
molecular signature.
Compared with patients older
than 40 years, on the other hand, AYA
patients in general have genetic and
molecular differences that confer a
more favorable prognosis.
As a patient ages, his or her ability to
tolerate certain medications critical to
the treatment of leukemia – particularly
ALL – also changes. Older patients often
are not able to tolerate high-intensity
regimens as well as children.
“Older patients have more toxicities
and also have a ‘biologically harder’
disease that is more resistant to the
standard treatments we have,” Dr. Stock
noted, “so treating ALL in AYA patients
poses a particular challenge.”
Psychosocial Challenges
As patients transition from adoles-
cence to adulthood, their lives become
exceedingly more complex – emotion-
ally, financially, and socially. People
at the lower end of the AYA age
spectrum may no longer be living at
home with their parents and might be
immersed in college life or beginning
their careers or families; people on
the higher end of the age spectrum
may be concerned about treatment
and side effects taking away time from
their family and careers.
All these factors complicate treat-
ment decisions and concerns about
treatment compliance, according to
Sumit Gupta, MD, PhD, a clinical
investigator at the Hospital for Sick
Children in Toronto.
“The psychosocial challenges are
significant,” he said. AYA patients
often are dealing with a blend of
factors unique to their age group,
like an increased focus on romantic
relationships, body image concerns, or
grueling school demands. “I have many
patients who don’t want to take steroids
because it can lead to weight gain, or
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