UP FRONT
Guest Column
The Roadmap Forward in Follicular
Lymphoma: Time for a Precision Approach
By Jonathan W. Friedberg, MD; Brad S. Kahl, MD; and John P. Leonard, MD
ver the past two decades,
improved diagnostic accuracy and novel therapeutic approaches have
resulted in profound
improvements in overall
survival in patients with follicular lymphoma (FL).
A 2013 study of patients diagnosed
with FL demonstrated a median overall survival exceeding 18 years.1 That
is nearly three times longer than that
reported in a study of FL patients diagnosed between 1981 and 1990, where
median overall survival with observation
or immediate chlorambucil treatment
was only 6.7 and 5.9 years, respectively;
furthermore, only 34 percent of patients
were alive at 10 years.2
Anti-CD20 monoclonal antibody
therapy may be largely responsible for this
improvement,3 but other new therapeutic
approaches (including bendamustine,4,5
lenalidomide,6 and hematopoietic cell
transplantation7) have also contributed
to longer survival among FL patients.
Whether or not any of these patients are
definitively cured outside of the setting of
allogeneic hematopoietic cell transplantation is not known, but as FL commonly
presents in older patients, death from
causes other than FL is becoming a more
frequent occurrence.
Seeking a New Endpoint
Traditional endpoints for oncologic drug
development have included complete and
partial response rates and progressionfree survival (PFS) – the latter of which
has been viewed by the U.S. Food and
Drug Administration as a surrogate for
both clinical benefit and overall survival.8
In a disease like FL, however, where
overall survival is now measured in
decades rather than months or years, it
is becoming increasingly challenging to
demonstrate clinical benefit with novel
therapeutic regimens when using PFS as
an endpoint.
Indeed, an international collaborative group has recently suggested that
complete response at 30 months is a good
surrogate for PFS in FL, proposing this as
a regulatory endpoint for new drug studies to improve feasibility and efficiency.9
ASHClinicalNews.org
Given the therapeutic progress in
FL, we feel a new paradigm is needed
for clinical research and an integration
of exciting novel therapeutics in FL. PFS
may no longer be a reasonable surrogate
for clinical benefit in this disease, given
that patients are frequently asymptomatic
and are likely to have outstanding overall
survival, with or without treatment.
Two recent randomized trials in low
tumor-burden FL are instructive in this
regard:10 Ardeshna et al. randomized
asymptomatic patients to either observation or two years of rituximab therapy,
and demonstrated (not surprisingly)
improved PFS in patients receiving rituximab treatment.11 However, the three-
Given the therapeutic progress
in FL, a new paradigm is needed
for clinical research and an
integration of
exciting novel
therapeutics in
this disease.
year overall survival was 97 percent
in both groups, and almost half of the
patients assigned to initial observation
had not required any treatment.
Kahl et al. randomized a similar
patient population who responded to
induction with single-agent rituximab
to a prolonged maintenance strategy, or
retreatment with rituximab upon progression.12 Although PFS was enhanced with
continuous – and expensive – rituximab
maintenance therapy, there was no
significant difference between the two approaches in terms of the time to failure of
rituximab treatment. As with the trial by
Ardeshna et al., overall survival was outstanding in both arms, but a quality-oflife analysis suggested no improvements
in anxiety and other measures for patients
on continuous treatment, calling the true
importance of “remission” in low-tumor
burden FL into question.13
Rewriting the Disease’s
Natural History
Given these recent observations, it is
clear that the vast majority of patients
with FL have very prolonged overall
survival and, given the asymptomatic
and non-morbid nature of their disease,
are at risk for overtreatment. However, certain subsets of patients remain
resistant to standard therapies and suffer
significant morbidity and mortality from
this disease.
In an analysis from the National
LymphoCare Study (NLCS), a longitudinal registry that enrolled more than 2,700
patients with FL between 2004 and 2007
and followed them for 10 years, the most
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