2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

What Is the Best Strategy for Incorporating
New Agents into the Current Treatment of
Follicular Lymphoma?
Overview: Although there is increasing knowledge about the
pathobiology of follicular lymphoma (FL), the incorporation of
new agents is challenged by the long clinical course and
inherent heterogeneity of the disease. Furthermore, a longstanding
concept in FL is that although most patients have an
indolent initial phase of disease, this is typically followed by
sequentially shorter remission durations and justifies the
continued intense search for new rationally designed agents.
Ideally, there would be personalized prognostic tools, preemptive
target identification, and means to predict response
in individual patients. Short of having these tools, one conceptual
approach is to consider FL as a series of clinical
disease states divided between treatment-naïve (low tumor
AS THE prototype of indolent lymphomas, follicular
lymphoma (FL) mandates a longitudinal perspective
when considering clinical management options. The median
life expectancy has improved, with approximately 40% of
patients surviving in excess of 10 years. 1,2 During this time,
patients can have variable clinical courses and, although
clinical prognostic indices are helpful, they are often difficult
to apply to individual patients outside of a research setting.
Furthermore, treatment decisions made early in the disease
may influence future options, and the optimal sequencing of
treatments is poorly defined. The traditional paradigm has
been that with each successive therapy, the duration of
response shortens until a blatantly chemoresistant picture
emerges. However, today a clearer understanding of FL
biology has led to the emergence of a new repertoire of
agents with more rational and targeted mechanisms of
action. These agents challenge the notion of inevitably
shorter response durations, and offer hope of improved
clinical outcomes compared with traditional sequential cytotoxic
therapy.
A major challenge to integrating new agents or new
approaches is the inherent clinical and biologic heterogeneity
of follicular lymphoma. Ideally, there would be personalized
prognostic tools, preemptive target identification, and
means to predict response in individual patients, followed by
randomized clinical trials validating each agent. Despite
major gains in dissecting the heterogeneity of FL (Table 1),
there are few existing ways of predicting an individual
patient’s overall disease course. One approach is to consider
FL not simply as one disease but as sequential clinical
disease states: treatment-naïve (low tumor burden and high
tumor burden), relapsed (chemoimmunotherapy-sensitive),
and multiply relapsed/chemoimmunotherapy resistant disease
(Fig. 1). At each point, the best approach to incorporating
new agents into the current treatment of FL requires an
understanding of pathogenetic mechanisms, a consideration
of the current and most promising agents, and conscientious
trial design in the context of desired patient outcomes. This
review will present a conceptual framework of clinical disease
states in FL, providing examples along the way of how
biologic insights and new agents are currently being integrated
into existing treatment paradigms.
By Sonali M. Smith, MD
burden and high tumor burden), relapsed (typically still
chemoimmunotherapy-sensitive), and multiply relapsed (usually
chemoimmunotherapy-resistant) disease. By applying
what is known about the biology of FL along with the available
agents, new treatment options can be better defined and
tested within these clinical contexts. During the last few
years, novel chemotherapeutics, biologic agents, monoclonal
antibodies, antibody drug conjugates, and maintenance strategies
are all either replacing or adding onto existing strategies.
These new agents and approaches challenge the notion
of inevitably shorter response durations, and offer hope of
improved clinical outcomes compared with traditional sequential
cytotoxic therapy.
Low–Tumor Burden FL (Treatment Naïve)
The vast majority of patients with FL have an asymptomatic
presentation, with either palpable or radiographically
visible adenopathy discovered incidentally. At initial diagnosis,
the pace of disease remains unknown for individual
patients, and there are no tools to accurately predict disease
behavior. Tumor grade is a rough measure of disease aggressiveness,
with FL grade 3b behaving akin to diffuse large
B-cell lymphoma. But for patients with FL grade 1 to 2,
comprising the bulk of patients, grade itself is a poor
predictor of outcome. The FL International Prognostic Indices
(FLIPI 1 and 2) are helpful, but it is important to
remember that all patients included in these retrospective
analyses were already being considered for therapy and
therefore do not adequately reflect a newly diagnosed,
asymptomatic patient with low tumor burden. 3,4 Newer
biologic markers may help identify patients at high risk for
aggressive disease behavior, but are far from routine application.
Despite these hurdles, low–tumor burden FL is an ideal
setting in which to evaluate novel agents or novel application
of existing agents. The National Lymphocare Study
found that nearly one-fifth of patients undergo a “watch and
wait” strategy, reflecting that no therapeutic intervention to
date has shown a survival benefit. 5 Strong support for
“watch and wait” can be derived from randomized trials that
had shown no advantage to early therapy. 6,7 Notably, these
studies were performed before the advent of monoclonal
antibodies, and the recent randomized trial of “watch and
wait” compared with a short course of the anti-CD20 monoclonal
antibody rituximab followed by a maintenance strategy
has reinvigorated the discussion regarding the timing of
treatment initiation in newly diagnosed, low–tumor burden
From the Section of Hematology/Oncology, Lymphoma Program, The University of
Chicago, Chicago, IL.
Author’s disclosures of potential conflicts of interest are found at the end of this article.
Address reprint requests to Sonali M. Smith, MD, Section of Hematology/Oncology,
Lymphoma Program, The University of Chicago, 5841 S. Maryland Ave., MC2115, Chicago,
IL 60637; email: smsmith@medicine.bsd.uchicago.edu.
© 2012 by American Society of Clinical Oncology.
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