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Guest Column
national Prognostic Index (FL-IPI) still
may have prolonged overall survival with
current therapeutic approaches.17,18
In the pre-rituximab therapeutic
era, certain biomarkers were proposed
(the presence of bcl-2 mutations and an
“immune-response-2” gene expression
profile) but have not been validated in
the modern era.19,20
Quality-of-life
measurements
to characterize
disease in lowerrisk patients will
be essential for
patients and
clinicians as
they apply new
agents to truly
provide benefit
beyond PFS.
Vitamin D insufficiency has been
validated as a predictor for inferior overall
survival in patients with FL treated with
R-CHOP,21 but whether this is indicative of
tumor biology, or a surrogate for generalized illness, is not yet known. A recent
effort to improve the clinical FL–IPI by
adding gene mutation status (called “M7FL–IPI”) has improved the fidelity of highrisk FL–IPI to some degree and represents
an important step in the right direction.22
However, more than 50 percent of patients
with high-risk disease according to the
M7 FL–IPI rating remain in remission two
years after R-CHOP, suggesting this still
may be an inadequate biomarker to truly
determine the subset of patients with FL at
highest risk for early death.
We feel that the most important
advances in FL moving forward will
come from understanding the underlying “high-risk” FL biology – including
the events leading to histologic transformation, a frequent cause of morbidity
and mortality – and applying precision
medicine approaches to this biologically defined subset. Large phase III
trials enrolling unselected patients with
advanced-stage FL that incorporate
prolonged maintenance approaches or
continuous treatment with expensive
medications and that use PFS should be
avoided. Even in the relapsed setting,
maintenance therapy has been shown
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ASH Clinical News
to improve PFS over observation after
bendamustine treatment, as seen in the
recently reported GADOLIN trial, but
this observations is unlikely to translate
ultimately to clinical benefit for an unselected group of patients.23
Defining the Unmet Needs of
Follicular Lymphoma Patients
For the majority of patients with FL who
will die with rather than from their disease
– and who have survival length similar
to their counterparts without lymphoma
– it is appropriate to consider rethinking
our therapeutic goals. Such patients may
receive numerous treatments over many
years, all of which may be associated with
acute, chronic, or long-term toxicities. If
the patient’s overall survival is not limited
by the disease, then the objective of
therapy should be to optimize his or her
quality of life.
To that end, our field is in need of
quality-of-life measurements that can
sufficiently characterize aspects of disease,
treatment-related side effects, and psychological and social factors (including
financial effects of therapy) to serve as a
primary endpoint for studies of novel approaches in lower-risk individuals. These
tools will be essential for patients and for
clinicians as they apply new agents and
regimens to truly provide meaningful
benefit beyond PFS.
To help the patients with greatest
need (those who are most likely to die of
FL), we propose to uniquely focus on the
high-risk population in the U.S. National
Clinical Trials Network.
First, we will study patients who
experience relapse within two years of
chemoimmunotherapy induction. In addition to exploring the role of novel therapeutic strategies (of which there are many
candidates24) in a prospective clinical trial
in this group of patients with known high
mortality, we also plan to bank diagnostic
tissue to extensively explore the biology of
these tumors. With these enriched tumor
banks for the high-risk population, we
hope to establish and validate optimal
biomarkers to identify these high-risk
patients at diagnosis and utilize rational
targeted therapeutic approaches in a
precision way.
We ask pharmaceutical sponsors and
international study groups to join us in this
important focused approach. If we are able
to substantially improve outcome in these
20 percent of FL patients, the majority of
deaths in FL will be avoided; the other 80
percent of patients are doing extremely well
with our current non-targeted therapeutic
paradigm, and may even be considered
for therapy de-escalation questions. Such
a precision approach will substantially
decrease costs of therapy, minimize morbidity, and truly provide clinical benefit for
patients with FL – an added value currently
missing from our empiric approaches to
treatment. ●
Jonathan W. Friedberg, MD, MMSc, is director of the
James P. Wilmot Cancer Institute and director of Hematologic Malignancies Clin