2012 EDUCATIONAL BOOK - American Society of Clinical Oncology

On the basis of encouraging data in relapsed patients, the
German Low-Grade Lymphoma Study Group compared bendamustine
and rituximab (BR) against rituximab, cyclophosphamide,
doxorubicin, vincristine, and prednisone (R-
CHOP) in 549 treatment-naïve indolent lymphomas, with
FL comprising more than half of patients. All patients
required therapy as per predefined criteria. Initially designed
as a noninferiority study, BR instead showed superior
complete response rates (40.1% vs. 30.8%; p � 0.03) and
PFS (54.8 vs. 34.8 months; p � 0.0002); with a median
follow-up time of approximately 3 years, there is a trend
toward improved overall survival. 17 The option to avoid
anthracyclines is appealing, particularly in a disease in
which the median age is in the sixth decade of life and
comorbidities often influence therapeutic choices. A confirmatory
trial of BR compared with rituximab, cyclophosphamide,
vincristine, prednisone (R-CVP) or R-CHOP recently
completed accrual (NCT00877006). For now, although it is
not clear that BR should be the front-line standard for all
patients in this disease state, it clearly provides a new
standard in terms of efficacy and tolerability for patients
with high tumor burden/symptomatic FL and is a platform
for new regimens. An Eastern Cooperative Oncology Group
(ECOG)-led study is evaluating BR with or without bortezomib
followed by rituximab with or without lenalidomide
as one example (NCT01216683).
Despite the high response rates to most chemoimmunotherapy
regimens, relapse is inevitable and has prompted
evaluation of maintenance or consolidation strategies. There
are currently two approved postremission strategies: maintenance
rituximab (on the basis of the PRIMA trial) and
consolidative radioimmunotherapy (on the basis of the FIT
trial). The PRIMA (Primary Rituximab and Maintenance)
trial provided clear evidence that maintenance rituximab,
even after a rituximab-containing chemotherapy induction,
could improve PFS (74.9% vs. 57.6%; p � 0.0001). However,
there was no improvement in overall survival. The FIT
(First-Line Indolent) trial delivered induction chemotherapy
(with or without rituximab) and then randomly assigned
patients to either 90 Y-ibritumomab tiuxetan or observation.
Patients in the consolidation arm had a significant conversion
of partial to complete remissions and a near-tripling of
PFS (13.3 vs. 36.5 months; HR � 0.465; p � 0.0001). 18 A
recent update of the FIT trial showed that PFS advantage
persists with 66-month median follow-up. 19 However, only
15% of patients received rituximab as part of their initial
induction. Two phase II studies support the addition of
consolidative 90 Y-ibritumumab tiuxetan after chemoimmunotherapy,
but a definitive phase III trial is lacking. 20,21 I 131
tositumumab consolidation has also been tested, with
clearly promising results after either CHOP or CVP
chemotherapy. 22-24 Mature follow-up of Southwest Oncology
Group (SWOG) protocol S9911 shows a 5-year PFS and
overall survival of 67% and 87%, respectively, which significantly
exceeds results for patients receiving treatment
without immunotherapy in prior SWOG studies. This promising
phase II trial prompted a randomized phase III trial of
CHOP with either rituximab or consolidative I 131 tositumumab,
which showed equivalence of both arms and overall
excellent outcomes. 25
Should all patients receive maintenance or consolidation
after chemoimmunotherapy? An unplanned but intriguing
subanalysis of the PRIMA trial evaluated the role of func-
484
tional imaging via fluorodeoxyglucose positron emission
tomography (FDG-PET) as a reflection of minimal residual
disease (MRD). 26 Thirty-two (26%) of 122 patients remained
PET positive at the end of induction. PET positivity was
strongly predictive of PFS (20 months vs. not reached; p �
0.001) and was more sensitive than standard computed
tomography (CT) criteria at identifying patients with an
inferior outcome. As a result of small numbers, it was not
possible to determine whether maintenance rituximab was
able to overcome post-induction PET positivity. However,
the use of PET in the PRIMA study reflects the general
interest in determining MRD status in FL as a predictor of
adverse outcome, and this might identify a population in
which new agents could be evaluated.
Several considerations regarding maintenance and consolidation
should be raised. First, if a front-line regimen has
greater relative efficacy, it is more difficult to demonstrate
the impact of a maintenance or consolidation strategy. As an
example, to date, there are no data showing that maintenance
or consolidation after BR is superior to observation
alone. Second, there are currently no data guiding the
selection of maintenance rituximab compared with consolidative
radioimmunotherapy. In addition, there are other
agents, such as lenalidomide or others (discussed later
herein), that are orally bioavailable, have encouraging
safety profiles, and show preliminary activity that should be
tested in this setting.
First and Second Relapse of FL
SONALI M. SMITH
Perhaps one of the most heterogeneous time points of FL
is the time of first or second relapse. At this point, disease
can be rituximab sensitive or resistant, and chemotherapy
sensitive or resistant. Patients with either an asymptomatic
or low-volume relapse generally receive treatment similar to
that of patients who are newly diagnosed, using chemoimmunotherapy
or biologic agents, whereas patients with a
quick relapse or aggressive course receive treatment similar
to that of patients with multiple relapses, as discussed in the
following pages. Similar to the front-line setting, there are
no readily available clinical or biologic markers to predict
outcome or select therapeutic regimens.
For many patients, the first or second relapse, particularly
if the duration of response to previous regimens has been
short, is the ideal time to consider autologous or allogeneic
hematopoietic stem-cell transplantation. Although this is
reviewed in detail elsewhere, it is important to note that
dose intensification with autologous stem-cell transplantation
has been a helpful tool for many patients in first or
second relapse. However, it is equally critical to note that
the vast majority of data were generated before the advent of
rituximab and that there are no randomized trials in the
modern era comparing autologous stem-cell transplantion
with chemoimmunotherapy regimens. Allogeneic stem-cell
transplantation is the only known curative modality for
relapsed advanced-stage FL, and a careful discussion of
potential risks and benefits with an experienced transplant
center should be considered for patients at early relapse,
particularly if there has been limited benefit to chemoimmunotherapeutic
regimens.
Similar to front-line settings, bendamustine is increasingly
used as a therapeutic backbone to which new agents
are added. One example is the addition of the proteasome
inhibitor bortezomib. The ubiquitin-proteasome pathway