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Follicular Lymphoma: Expanding Therapeutic Options

Follicular Lymphoma: Expanding Therapeutic Options

ABSTRACT: The most common indolent lymphoma, follicular lymphoma comprises 35% of adult non-Hodgkin’s lymphoma (NHL) in the United States and 22% worldwide. Features associated with adverse outcome include age, male gender, disease stage, and performance status, with the International Prognostic Index being the most widely used risk classification system. Long-term disease-free survival is possible in select patient subgroups after treatment, but very late relapses suggest that quiescent lymphoma cells might be harbored for long periods of time. Radiation therapy is the mainstay of treatment for limited-stage follicular lymphoma, but there is some experience with chemotherapy and combined chemoradiation. When to initiate treatment in patients with advanced disease is controversial, but options include various combined chemotherapy regimens, monoclonal antibodies, radiolabeled antibodies, and bone marrow or stem cell transplantation. Future directions in the treatment of follicular lymphoma include vaccines, antisense therapy, and proteasome inhibitors.

Follicular lymphoma is a type
of non-Hodgkin's lymphoma
(NHL) that arises from the follicle
center B lymphocytes and has a
follicular pattern on histopathologic
examination.[1] It is the most common
indolent lymphoma, comprising 35%
of adult NHL in the United States and
22% worldwide.[2] It most commonly
is seen in middle-aged individuals and
the elderly, with a median age of diagnosis
of 59 years, as compared to
64 years for patients with diffuse large
B-cell lymphoma. Females (52%) are
slightly more often affected than males
(48%).[3,4]

Morphologically, follicular lymphoma
is composed of a mixture of
centrocytes (cleaved follicle center
cells) and centroblasts (large noncleaved
follicle center cells), with
centrocytes being the predominant cell
type and centroblasts being in the minority.[
5] The most reproducible
method of grading follicular lymphoma,
as described by Berard and Mann,
is based on the absolute number of
centroblasts in 10 neoplastic follicles,
expressed per 40* high power field
(hpf): grade 1 is defined as 0-5 centroblasts/
hpf; grade 2, as 6-15 centroblasts/
hpf; and grade 3, as > 15
centroblasts/hpf.[6] Clinically, the
behavior and outcome of grades 1
and 2 follicular lymphoma are similar,
and both are considered indolent
lymphomas. In contrast, grade 3 is a
more aggressive disease.[7]

Patients usually present with diffuse,
painless, persistent, generalized
lymphadenopathy, and except for
bone marrow involvement, extranodal
disease is uncommon. The size of
the lymph nodes may vary with time,
and complete disappearance followed
by reappearance has been reported.
The Ann Arbor staging system developed
in 1971 for Hodgkin's disease
has been adapted for staging
NHL as well.[8,9] In a retrospective
analysis, Anderson et al found that clinically,
66% of patients had stage III
disease, whereas pathologically, 84%
of patients had stage III/IV disease at
presentation.[10]

Prognostic Features

A large number of features have
been associated with an adverse outcome
in follicular lymphoma, including
increased age, male gender, stage
of disease, performance status, presence
of B symptoms, elevated levels
of serum lactate dehydrogenase
(LDH), serum beta-2 microglobulin,
and hemoglobin, as well as bulk disease
and extranodal involvement. The
most widely used system is the International
Prognostic Index (IPI). According
to the IPI, age > 60 years,
stage III/IV disease, Eastern Cooperative
Oncology Group (ECOG) performance
status < 2, involvement of
more than two extranodal sites, and
elevated serum LDH levels are
considered adverse prognostic factors.[
11] In a Spanish study, 10-year
overall survival rates were 74% for
low, 45% for low-intermediate, 54%
for high-intermediate, and 0% for
high-risk groups based on IPI score
(P < .001).[12]

In 1991, Romaguera et al developed
a model based on the tumor burden
to predict outcomes in follicular
lymphoma. The investigators included
number of extranodal sites involved,
degree of bone marrow
involvement, and lymph node size in
this model, and found that patients
with a low tumor burden had a 10-year
survival of 73% as compared to 24%
for those with a high tumor burden.[
13] Decaudin et al studied 484
patients with stage III/IV follicular
lymphoma, identifying three prognostic
factors for poor overall survival: B
symptoms, age greater than 60 years,
and at least three nodal sites greater
than 3 cm.[14] Frederico et al devised
a prognostic model based on age, gender,
number of extranodal sites, B
symptoms, serum LDH level, and
erythrocyte sedimentation rate. They
found a 5- and 10-year survival rate
of 90% and 65% for patients at low
risk, respectively; 75% and 54% for
patients at intermediate risk; and 38%
and 11% for those at high risk.[15]

In a recent retrospective analysis
of 810 patients treated with anthracycline-
based chemotherapy and adjuvant
radiotherapy to sites of initial
bulky nodal disease, only three factors-
age > 60 years, presence of B
symptoms, and involvement of more
than two extranodal sites-were found
to influence overall and progressionfree
survival. When the IPI was applied
to these patients, no statistical
differences were observed in outcomes
between the various groups.
This suggests a lack of uniform prognostic
factors for follicular lymphoma,
indicating an urgent need for
multicentric international clinical analysis
to define prognostic factors.[16]

Recently, an international group
looked at a variety of prognostic
factors in a large number of patients
with follicular lymphoma and found
that age ≥ 60 years, stage III/IV disease,
elevated LDH level, hemoglobin
< 12 g/dL, and number of nodal
sites ≥ 5 had a significant adverse
effect on survival. They designed an
index based on these factors: the Follicular
Lymphoma International Prognostic
Index (FLIPI). Based on the
FLIPI, patients could be divided into
three prognostic groups: good (0-1
adverse prognostic factor), intermediate
(2 factors), and poor (≥ 3 factors).
The 10-year overall survival was
70.7%, 50.9%, and 35.5%, respectively
for the three groups (Table 1).[17]

The role of histopathology in predicting
outcome is much more controversial.
It is generally agreed that
the presence of large cells confer a
more aggressive nature to follicular
lymphoma.[18,19] The degree of nodularity
has also been studied as a prognostic
factor. In an ECOG study, a
pure nodular pattern (defined as nodularity
involving 75% or more of the
cross-sectional area) was found to be
an important favorable prognostic indicator
as compared with a nodulardiffuse
pattern.[20] Similarly, Hu et
al from Stanford University found that
patients with focally follicular areas
(ie, < 25% of the histologic section)
had significantly worse outcomes
compared with patients with a predominantly
follicular architecture (ie,
> 50% of the section).[21]

Another recent study from the University
of Nebraska found that cases
of follicular lymphoma (grade 3) with
a predominant diffuse component
(> 50%) had a significantly worse
overall and event-free survival (similar
to diffuse large B-cell lymphoma)
than those without.[22] Martin et al
studied the prognostic value of proliferative
index in 106 patients with
follicular lymphoma. They determined
the proliferative index quantitatively
using an automated image
analyzer and found that patients with
a low proliferative index (< 40%) had
a significantly longer overall survival
than those with a high proliferative
index (≥ 40%), but the proliferative
index did not predict failure-free
survival.[23]

Clinical Course

Horning and Rosenberg studied 83
asymptomatic patients with low-grade
NHL (most of whom had follicular
lymphoma), in whom the advanced
disease was initially managed without
therapy. The 5- and 10-year actuarial
survival rates were 82% and 73%,
respectively, and spontaneous regressions
occurred in 19 untreated patients.[
24] Portlock and Rosenberg
retrospectively studied 44 asymptomatic
patients with stage III/IV NHL
who received no initial treatment.
They found that the median time to
treatment was 31 months, and the
median survival was 121 months. The
4-year actuarial survival was
77.3%.[25] More recently, in a retrospective
study conducted at Stanford
University, Advani et al studied 43
patients with stage I/II follicular lymphoma
who were not treated initially.
They showed in this study that deferred
therapy is an acceptable approach
for patients with early-stage
disease.[26]

Some authors have stated that conventional
chemotherapy is neither curative
nor does it substantially modify
the natural course of follicular lymphoma.[
27] Patients with disseminated
disease ultimately die from the
disease, with a median survival time
of 8 to 10 years.[28] However, longterm
disease-free survival (relapsefree
survival of ~50%) has been noted
in a number of settings, ie, limitedstage
disease, grade 3 follicular lymphoma
(unpublished data), achievement
of complete remission following
chemotherapy or concomitant chemotherapy
and radiation therapy (RT),
and following autologous stem cell
transplantation.[29-34]

Whether one considers follicular
lymphoma to be curable depends on
the definition of cure. If one considers
clinical cure (ie, the absence of a
clinically obvious relapse) as the criterion,
this has been demonstrated in
various groups of patients who have
had a long-term disease-free survival
following various interventions as
mentioned above. However, since follicular
lymphomas have an extremely
indolent course, it is very difficult to
determine if clinical cure corresponds
to complete elimination of all lymphoma
cells.

In addition, patients in clinical remission
can have small numbers of
circulating lymphocytes exhibiting
t(14;18) translocations that are considered
pathognomonic of follicular
lymphoma.[35] However, these cells
can also be identified in the peripheral
blood of healthy individuals. Schuler
et al found that if the sensitivity of
the assay used for detection was high
enough in almost all healthy individuals,
one or multiple cell clones carrying
the t(14;18) translocation could
be found.[36]

Thus, long-term disease-free survival
is possible after treatment of patients
with follicular lymphoma, but it is impossible
to be sure that this corresponds
to the absence of even a single lymphoma
cell in the patient. Very late relapses
suggest that some patients might
harbor quiescent lymphoma cells for
very long periods of time.

Treatment of
Limited-Stage Disease
No Initial Treatment
In a French study, Brice et al randomized
193 newly diagnosed follicular
lymphoma patients with a low
tumor burden to no initial treatment,
prednimustine, or interferon alfa-2b
(Intron A) and found no difference in
the overall survival rate at 5 years
among the three groups.[37] In the Stanford
study described above, Advani et
al found that at a median follow-up of
86 months, 27 patients (63%) had not
yet required treatment.[26]

Radiation Therapy
Radiation therapy has been the
mainstay of treatment for limited-stage
grade 1 and 2 follicular lymphoma.
Table 2 presents an overview of the
clinical trials that have used RT as the
major modality for treatment.[38-49]
The results of these studies uniformly
show that involved-field RT confers
a 10-year failure-free survival of approximately
45% in patients presenting
with early-stage disease.

Chemotherapy
The role of chemotherapy alone in
the treatment of early-stage follicular
lymphoma is not exactly clear. Jeffery
et al treated 30 patients with nonbulky
stage I, nodal, intermediate-grade NHL
with RT. They then compared the outcomes
in 11 patients with bulky stage I
disease treated with combination chemotherapy.
They found that the
5-year actuarial survival for the 30
patients treated with RT was 86%, as
compared to a 60% 4-year actuarial
survival in the 11 patients treated with
chemotherapy.[50] In contrast, Teczan
et al evaluated 40 patients with previously
untreated follicular lymphoma
and found that stage IA patients treated
with chemotherapy (with or without
RT) showed a better trend for
10-year event-free survival as compared
to RT alone. There was, however,
no difference in the estimated
10-year overall survival.[51]

Combined Chemoradiation
In a study conducted at Memorial
Sloan-Kettering Cancer Center,
Yahalom et al randomized 44 patients
with clinical or pathologic stage I
intermediate-grade or low-grade NHL
to receive regional RT alone or regional
RT followed by six cycles of
CHOP chemotherapy (cyclophosphamide
[Cytoxan, Neosar]/doxorubicin
HCl/vincristine [Oncovin]/prednisone).
They found an 83% actuarial
relapse-free survival rate for the
RT-plus-CHOP group at 7 years,
compared with 47% for the RT-alone
group. The overall survival for the
two groups was 88% and 66%, respectively.
However, in patients with
low-grade NHL, the addition of adjuvant
CHOP did not improve
outcomes.[52]

McLaughlin et al prospectively
treated 44 patients with stage I/II lowgrade
lymphoma with sequential chemotherapy
and involved-field RT. At
a median follow-up of 32 months,
they had 5-year overall and failurefree
survival rates of 89% and 74%,
respectively.[53] Seymour et al studied
102 eligible patients with stage I/II
low-grade lymphoma (85 patients with
follicular lymphoma) treated with chemotherapy
and involved-field RT.
They found that the 10-year time to
treatment failure and overall survival
rates in patients with follicular lymphoma
were 72% and 80%, respectively.[
54] These results constitute a
marked improvement in the 10-year
disease-free survival of 41% to 64%
reported by the various studies involving
RT alone described above.

Richards et al retrospectively studied
202 patients with clinical stage I/II
NHL between 1972 and 1985. They
found that although the duration of
remission was better in patients who
received adjuvant chemotherapy than
in those treated with RT alone, there
was no difference in overall survival
between the two groups of patients.
Since neither of these were randomized
trials, it is unclear whether the
addition of chemotherapy would improve
the outcomes obtained by RT
alone.[55]

Treatment of Advanced DiseaseNo Initial Treatment
The exact time to initiate treatment
in this setting is controversial, since
these patients have a prolonged survival
despite frequent relapses. In an
effort to answer the question of whether
early aggressive therapy is superior
to watchful waiting, the National
Cancer Institute (NCI) conducted a
study in 104 patients with advanced
indolent lymphomas. They randomly
assigned 44 patients to the watchful
waiting group, in which only carefully
defined, limited RT was administered
if necessary; 45 were randomly
assigned to aggressive combinedmodality
treatment with ProMACEMOPP
(prednisone, methotrexate,
doxorubicin, cyclophosphamide,
etoposide, mechlorethamine [Mustargen],
vincristine, procarbazine [Matulane],
prednisone), followed by total
nodal irradiation. They found no difference
in overall survival at 5 years
(> 75% in each group), but diseasefree
survival was better in the group
that received initial therapy.[56]

In a recently published British
study, Ardeshna et al randomized 309
patients with asymptomatic, advancedstage,
low-grade NHL (204 patients
with follicular lymphoma) to immediate
systemic chemotherapy with
chlorambucil (Leukeran), 10 mg/d
continuously, vs an initial policy of
observation with systemic therapy
delayed until disease progression.
However, in contrast to the above
study, they found that overall survival
and cause-specific survival did not
differ between the two groups.[57]

Chemotherapy

  • CVP-Systemic chemotherapy is
    the mainstay of treatment in patients
    with advanced-stage follicular lymphoma.
    Hoppe et al randomized 51
    patients with favorable-histology NHL
    (pathologic stage III/IV disease) to
    single-alkylating agent chemotherapy,
    combination chemotherapy with
    CVP (cyclophosphamide, vincristine,
    prednisone), or fractionated wholebody
    irradiation followed by low-dose
    involved-field irradiation. They found
    an actuarial survival of 84% at 4 years,
    with similar survival observed for each
    of the three treatment options.[58]
  • Kennedy et al randomized 58 patients
    with advanced lymphoma to the
    CVP combination or these same three
    agents given separately in succession.
    They demonstrated a complete remission
    rate of 81% with the combination
    and 46% with sequential use of
    the three agents.[59] Portlock et al
    randomized 63 previously untreated
    patients with stage IV NHL with favorable
    histologies to three groups:
    CVP alone, split-course CVP and total
    lymphoid irradiation, or single-
    alkylating agent therapy. The actuarial
    probability of obtaining a complete
    remission was greater than 80% in all
    three groups. In contrast to the above
    findings of Kennedy et al, they found
    no statistically significant differences
    among the groups in terms of the
    probability of disease-free or overall
    survival.[60]

  • CHOP-Peterson et al randomized
    228 patients with stage III/IV follicular
    lymphoma to cyclophosphamide
    or the CHOP-B combination (cyclophosphamide,
    doxorubicin, vincristine,
    prednisone, bleomycin [Blenoxane]).
    These investigators observed complete
    responses in 66% of those treated with
    cyclophosphamide and in 60% of
    those treated with CHOP-B. They
    found no difference in overall survival
    between the two groups. However,
    in an unplanned subgroup
    analysis, patients with follicular
    mixed lymphoma who received the
    combination experienced improved
    disease control and survival.[61]
  • Jones et al compared two CHOP
    regimens (CHOP with either low-dose
    bleomycin or bacille Calmette-Gurin
    [BCG] by scarification) to COP-Bleo
    (cyclophosphamide/vincristine/prednisone,
    with low-dose bleomycin). In
    patients with follicular lymphoma,
    they found no difference in complete
    response rates, relapse-free survival,
    and overall survival among the three
    groups.[62]

  • Other Combinations-In an effort
    to improve outcomes in this setting,
    other regimens have been tried. Ezdinli
    and associates analyzed 252 patients
    with advanced-stage favorable NHL
    treated with moderate-CP (cyclophosphamide,
    prednisone)-vs intensive-
    BCVP (carmustine [BCNU,
    Gliadel], cyclophosphamide, vincristine,
    prednisone) or COPP (cyclophosphamide,
    vincristine, procarbazine,
    prednisone)-chemotherapy regimens.
    They found an overall complete
    response rate of 57% and a median duration
    of remission of 88 weeks. There
    was no difference in the response rate,
    response duration, or survival rate
    among the various groups.[63]
  • In a recent Italian study, Zinzani et
    al performed a comparative trial of
    FM (fludarabine [Fludara], mitoxantrone
    [Novantrone]) with CHOP
    as front-line chemotherapy, with and
    without sequential rituximab (Rituxan).
    They randomized 140 previously
    untreated patients with grades 1 and 2
    follicular lymphoma to either CHOP
    or FM. The overall clinical response
    was the same in both groups (FM:
    96%; CHOP: 98%). However, the
    complete response rate was higher in
    the FM arm (68% vs 42%; P = .003).
    They also found that the percentage
    of patients with a negative bcl-2/immunoglobulin
    heavy chain (IgH) status
    by qualitative polymerase chain
    reaction was higher in the FM group
    (47% vs 29%; P = .03). These results
    seem to indicate that FM may be superior
    to CHOP for front-line therapy
    of follicular lymphoma. However, it is
    unclear whether this superiority translate
    into superior progression-free or
    overall survival.[64]

  • Interferon-Interferon has been
    tried alone and in combination with
    cytotoxic chemotherapy for the treatment
    of advanced follicular lymphoma.
    The individual studies are summarized
    in Table 3.[37,65-72] Rohatiner
    et al performed a meta-analysis of these
    clinical trials involving interferon.
    Their initial meta-analysis showed an
    overall survival difference in favor of
    interferon, but a significant heterogeneity
    effect suggested significant differences
    between trials.
  • The investigators then divided the
    trials based on the interferon dose used
    and found that trials using a more intensive
    therapy showed a large and significant
    survival advantage in favor of
    interferon, with a 14% survival difference
    at 5 years (74% vs 60%) and a
    19% survival difference at 8 years
    (57% vs 38%). However, trials that
    used a low-intensity interferon regimen
    showed no survival difference.[
    73] The results with the use of
    interferon are mixed, thereby leading
    to controversy about the exact role of
    interferon in the treatment of advanced
    follicular lymphoma.

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