ARTICLE
Auteur(s) : Antoine Italiano, Antoine
Thyss
Centre régional de lutte contre le cancer Antoine-Lacassagne,
département d’hématologie, 33, avenue de Valombrose, 06189 Nice
cedex 2, France
Follicular lymphoma (FL) represents approximately 25% of all adult
non-Hodgkin’s lymphomas (NHL) in Western countries. According to
earlier NHL classifications, FL has been considered as low-grade
malignant B cell lymphomas usually characterized by an indolent
course with a continuous pattern of relapse and a median survival
of 10 years but it can almost never be cured with conventional
treatment.Some FL patients have poor progression-free (PFS) and
overall survival (OS) rates, suggesting that this group is not
homogeneous. To develop a prognostic system based on uniform
criteria for patients with follicular lymphoma, an international
co-operative study was undertaken in 1999 [1]. An analysis of
prognostic factors was carried out on 4,167 patients from 27
centres in Europe and the USA. Multivariate analysis identified
five factors with the largest adverse prognostic influence on
survival and these were selected to build the index: age > 60
years, number of nodal sites > 5, serum LDH level greater than
upper limit of normal, haemoglobin level < 12 g/dl and Ann Arbor
stage III-IV. Using these five factors, the Follicular Lymphoma
International Prognostic Index (FLIPI), defined three risk groups:
- – low-risk (0-1 adverse factor, 36% of patients, 10-year
survival of 70.7%)
- – intermediate-risk (2 factors, 37% of patients, 10-year
survival of 51%)
- – poor-risk (≥ 3 adverse factors, 27% of patients,
10-year survival of 35.5%).
The FLIPI was tested in another group of 1,000 patients and its
reproducibility was confirmed. The FLIPI appears to be more
powerful than the IPI but it was established on a population of
patients treated with conventional therapies such as
anthracyline-containing chemotherapy regimens or radiotherapy. For
this reason its validity should be confirmed with the new
therapeutic approaches recently developed such as monoclonal
antibodies, radioimmunotherapy, or intensive therapies with stem
cell transplantation.This review summarizes the recent data of the
literature in relation with the treatment of FL.
Localized disease
Patients with localized disease at presentation (stage I/II) should
be offered definitive irradiation as the present standard of care
[2]. All the series demonstrate greater than a 40% freedom from
treatment failure with a 10 year follow-up. Median survival
ranges between 13 and 16 years [3-6]. After 10 years,
recurrences are rare (approximately 10%) suggesting that a
proportion of patients might be cured of their disease.
The role of adjuvant chemotherapy remains unclear. At least four
randomized studies have failed to demonstrate a survival advantage
with this modality [7-10]. However, recently, Seymour et al. have
updated results on their combined–modality therapy with
cyclophosphamide, vincristine and prednisolone + bleomycin or
cyclophosphamide, doxorubicin, vincristine and prednisolone +
bleomycin in addition to radiotherapy in patients with early stage
follicular NHL [11]. In this study the ten year freedrom from
treatment failure and overall survival rates were 72 and 80%,
respectively. These results are superior to those previously
reported with radiotherapy alone. Some authors have advocated
adjuvant chemotherapy for selected stage II patients with
unfavourable prognostic factors, such as systemic symptoms or more
than two nodal sites, and for those with follicular mixed
histology. Future trials will help to evaluate this option.
Disseminated disease
At diagnosis, approximately 80% of patients with FL have
disseminated disease with one or more extranodal localizations (Ann
Arbor stage IV), corresponding most often to bone marrow
involvement. Until recently, advanced FL was universally considered
as an incurable disease. The rate of relapse is fairly consistent
over time, even in patients who have achieved complete response to
treatment. The optimal treatment strategy in patients with
disseminated disease remains controversial. In patients with
asymptomatic advanced stage FL, a watch-and-wait policy is an
appropriate option according to the results of three randomised
studies that showed no benefit of early treatment over a watchful
waiting approach [12-14]. High tumour burden could be defined by at
least one of the following GELA (Groupe d’étude des lymphomes de
l’adulte) criteria [15]:
- – B symptoms
- – ECOG performance status > 1
- – LDH > normal range
- – serum beta-2 microglobulin > 3 mg/l
- – largest nodal or extra nodal mass greater than
7 cm
- – significant serous effusions detectable clinically or
on chest x ray
- – symptomatic spleen enlargement
For these patients with high tumour burden, therapeutic options
include: chemotherapy, monoclonal antibodies, radioimmunotherapy,
autologous or allogeneic stem cell transplantation. These options
are currently being evaluated in the scope of clinical trials.
Chemotherapy
When a decision is made to treat a patient with disseminated FL
using cytotoxic chemotherapeutic agents, a wide variety of choices
is available. These include single agent chlorambucil,
cyclophosphamide or fludarabine with or without prednisone, or
combinations chemotherapy regimens such as CVP (cyclophosphamide,
vincristine and prednisone), CHOP (cyclophosphamide, vincristine,
doxorubicin and prednisone) and fludarabine-containing combinations
(fludarabine and mitoxantrone or fludarabine and cyclophosphamide
with or without prednisone). Each of these approaches produces high
objective responses rates with 20-70% of complete responses. The
median complete response duration is approximately 3 years but
25% of complete responders remain free of disease after
10 years.
The CHOP regimen is the standard chemotherapy regimen for adults
with diffuse large-B cell lymphoma [16]. This combination has also
been widely used in FL but the impact of anthracyclines in
combination chemotherapy regimens on disease outcome remains
unclear. Five randomised trials have evaluated whether either
doxorubicin or mitoxantrone might improve outcome. The trial with
mitoxantrone [17] showed borderline significance in terms of
freedom from progression but overall survival data were not
presented. The four remaining trials [18-21], which evaluated a
doxorubicin-containing regimen were negative except for a
significant increase of response rate in one study [20]. Moreover,
a retrospective study by Dana BW et al. [22] reviewed survival data
of patients with low-grade lymphoma and their conclusion was that
doxorubicin-containing regimens did not prolong overall survival of
low-grade lymphoma patients. Contradictory results were reported by
Rigacci et al. in a retrospective study [23] which showed that
patients with FL treated with an anthracycline-containing regimen
had a better outcome compared to patients treated with other
combination regimens in terms of complete responses, overall
survival and failure free survival (FFS). Fludarabine in previously
untreated patients is an extremely active drug with a complete
response rate of almost 40% as a single agent and ranging from 44
to 89% in combination with cyclophosphamide or mitoxantrone [24,
25].
Following relapse, FL continue to be sensisitive to
chemotherapy, but median the PFS decreases with each subsequent
relapse [26]. Several second-line chemotherapy regimens have been
used in patients with FL. Fludarabine-containing regimens, often
used in this situation [24, 25], have demonstrated better
progression free survival, treatment free survival and social
function scores than those observed with CVP [27].
Immunotherapy with anti-CD20 antibodies
The introduction of monoclonal antibodies (mAb) has dramatically
expanded the therapeutic armamentarium in the treatment of
non-Hodgkin’s lymphoma and there is now an explosion of clinical
data regarding their use. Rituximab is a humanized anti-CD20
monoclonal antibody and has significant activity in follicular
lymphoma. Proposed mechanisms of action include antibody-dependent
cellular toxicity, complement-mediated cytotoxicity and induction
of apoptosis.
Three recent clinical trials have adressed the efficacy of
rituximab monotherapy in previously untreated indolent lymphomas?
mostly in advanced disease [28-30].The results are
summarized in table 1( Table 1 ).
Response rates in these studies ranged between 61 and 73% and the
CR rates between 26 and 37% with documented molecular responses.
These trials using single-agent rituximab as first-line treatment
have demonstrated high response rates with a favourable safety
profile. By virtue of its low toxicity profile and considering the
limited data suggesting that longer response durations can be
achieved by the use of more cycles of rituximab than with the
standard 4-cycle course, two recently reported trials have
evaluated the ability of maintenance rituximab to improve outcome
of FL patients [31, 32]. Both studies indicate that rituximab
maintenance therapy does offer a progression-free-survival benefit
in the treatment of FL. However a number of questions remains to be
adressed. What is the optimal maintenance schedule? Is maintenance
superior to re-treatment at time of progression? What is the value
of rituximab maintenance following combination immunochemotherapy?
Ongoing and future trials will help to answer these questions.
In patients with relapsed or refractory FL treated with
rituximab 375 mg/m2 once weekly for 4 weeks,
overall response rates ranged from 21 to 63% but only a minority
(3-23%) had a CR [33-41]. In the pivotal trial, the response rate
was 60% with 6% CR [34]. Interestingly, re-treatment with rituximab
is feasible and efficient with a response rate in the 40% range in
patients who had received at least one earlier course of rituximab
[42-44].
Table 1 Rituximab monotherapy as first-line treatment
|
Author
|
Patients
|
Follow-up
|
RR (CR)
|
DFS 3 years
|
OS 3 years
|
|
Colombat et al. [27]
|
49
|
NA
|
73% (26%)
|
32%
|
NA
|
|
Hainsworth et al. [28]
|
60
|
30 months
|
47% (7%)
|
49%
|
NA
|
|
Witzig et al. [29]
|
37
|
31 months
|
72% (36%)
|
22,5%
|
NA
|
Immunotherapy
A number of important features support the rationale for a combined
immunochemotherapeutic approach using rituximab and conventional
chemotherapy for the treatment of FL:
- – efficacy of immunotherapy as a single agent,
- – mechanisms of action are not cross-resistant,
- – synergy between rituximab and chemotherapy,
- – chemosensitization associated with rituximab,
- – no decrease in chemotherapy dose-intensity,
- – non-overlapping toxicities.
Based on impressive response rates approaching 100% in many
phase II studies evaluating
this approach, a number of prospective randomised trials have
been conducted to compare the
efficacy of rituximab plus standard chemotherapy with
chemotherapy alone. The German Low Grade Lymphoma Study Group has
recently reported the results of a phase III trial showing
that addition of rituximab to CHOP chemotherapy results in a
significant increase of
time to treatment failure [45], which was 2.6 years in the CHOP
arm, and greater than 3 years for R-CHOP, with comparable
toxicity. Similar results were reported by Marcus et al. in a
randomised study comparing CVP with the same regimen plus rituximab
[46]. In the case of pretreated FL patients, Forstpointner et al.
have recently published the results of a prospective randomised
comparison of fludarabine, cyclophosphamide and mitoxantrone versus
the same regimen plus rituximab showing a significant improvement
in progression-free-survival in the group receiving rituximab [47].
In all these trials, treatment-related side effects predominantly
comprised grade 3/4 myelosuppression with no differences between
study arms and very few severe infectious complications. In
summary, immunochemotherapy is a very promising approach to the
treatment of FL but longer follow-up is required to confirm this
benefit in terms of overall survival.
Interferon
Interferon (IFN) has been used concurrently with other
chemotherapeutic regimens and as maintenance therapy after
remission has been obtained. A recent meta-analysis [48] showed a
significant benefit for survival in favour of IFN alpha especially
when it is given (i) in conjunction with relatively intensive
initial chemotherapy, (ii) at a dose ≥ 5 million units, (iii)
at a cumulative dose of > 36 million units/28 days, (iiii)
with chemotherapy rather than as maintenance therapy. However, use
of IFN must be tempered by the frequent poor tolerance especially
with regard to the limited improvement in outcome which represents
a gain of 12.3 months of PFS and 7.4 months of OS in a
quality-of-life adjusted survival analysis published by Cole et al.
[49].
Radioimmunotherapy
Radioimmunotherapy (RIT) is a particularly attractive approach for
the treatment of FL because in addition to promoting antitumor
activity through antibody-mediated mechanisms, it has the ability
to target a patient-specific dose of radiation to the tumor with
minimal toxicity to normal organs. The safety and efficacy of RIT
have been established in the treatment of relapsed or refractory
indolent non-Hodgkin’s lymphoma. Zevalin® was the first
RIT agent to be approved by the US Food and Drug Administration and
Bexxar® has recently been approved.
Witzig et al. compared the efficacy of Zevalin® with
rituximab monotherapy in a randomised phase III trial in patient
with relapsed or refractory CD20 + B cell NHL [40].
Zevalin® was particularly effective in the 113 patients
with FL in whom the overall response rate was 86% with a 55% rate
in the rituximab group (p < 0,001). The therapeutic efficacy of
Bexxar® was demonstrated in four multicenter trials in
patients with relapsed and refractory low-grade and transformed
low-grade NHL [50]. In all these trials, treatment with
Bexxar® produced high overall and CR rates depending on
the extent of prior therapy and many responses were of long
duration. The multicenter open-label trial was conducted in
60 patients with refractory low-grade NHL [50]. Patients in
the trial had received at least two different chemotherapy
treatments and had failed to respond to or had relapsed within
6 months after their last qualifying chemotherapy. It was
shown that the response rate and response duration achieved with
Bexxar® were significantly greater than those achieved
with the last qualifying chemotherapy (65 versus 28% overall
response rate, 20 versus 3% CR, median response duration of
6.5 months versus 3.5 months respectively). RIT with
Bexxar®[51] or Zevalin®[52] also has
demonstrated safety and efficacy in patients who either failed to
respond to rituximab or relapsed following treatment with
rituximab.
On the basis of these results, several investigators have
explored the feasibility of administering Bexxar® or
Zevalin®, combined or not with chemotherapy to patients
with newly diagnosed FL. Recent results are encouraging with
complete responses rates ranging between 74 and 86% [53-57]. The
magnitude of clinical benefit and myelotoxicity of
Bexxar® and Zevalin® seem to be comparable
and it is unlikely that there will ever be a direct comparison of
the two products, since it would be take a very large study to
determine small efficacy differences, if they exist.
Autologous stem cell transplantation (ASCT)
Jonhson et al. have clearly demonstrated that, after each
subsequent relapse of FL, the response rate to treatment decreases
and the progression-free survival time shortens [26]. This explains
why most intensive therapies have been performed in patients with
disseminated disease who have either not responded to initial
conventional treatment or relapsed after one or more regimens of
chemotherapy. For this reason the contribution of ASCT has been
investigated in numerous phase II trials and retrospective
analyses. However, only one randomised trial has compared intensive
and conventional therapy in pretreated patients [58]. Patients with
follicular lymphoma who relapsed after receiving first-line therapy
and had entered complete or partial remission with subsequent CHOP
chemotherapy were assigned to either three further cycles of CHOP,
or cyclophosphamide and total-body irradiation followed by
haemopoietic stem-cell rescue, with or without in vivo purging with
rituximab. A significant improvement in progression-free survival
and overall survival was shown for patients receiving high-dose
therapy compared with patients receiving CHOP. However, the number
of patients accrued was small, and the number randomised even
smaller precluding any analysis of the benefit of purging.
Recently, the autologous stem cell transplantation procedure has
become easier and cheaper. As treatment-related mortality is very
low (about 2%), one attractive approach is to propose ASCT as
front-line therapy. Three randomized studies comparing conventional
chemotherapy versus ASCT have been published, one of them only
under abstract form (table 2)( Table 2
). The German Low-grade Non-Hodgkin Lymphoma Study Group has
reported preliminary results indicating a significant improvement
in five-year PFS for patients treated with HDT (64.7 versus 33.3%,
p < 0.0001) after a median follow-up of 4.2 years [59].
Results concerning overall survival are still blinded because of
the short median follow-up. Two others trials conducted by the
Groupe d’étude des lymphomes de l’adulte (GELF 94 trial) [60]
and the Groupe Ouest-Est pour l’étude des leucémies aiguës et des
maladies du sang (GOELAMS 064 trial) [61] compared standard
conventional immunochemotherapy (a CHOP-like regimen concomitantly
associated with interferon alpha) versus high-dose chemotherapy
with the transplantation of either unselected (GELF 94) or
purged (GOELAMS 064) peripheral stem cells. Updated results
have shown respectively an improvement in overall survival in the
GELA trial and only in progression-free-survival with no benefit in
overall survival in the GOELAMS study.
In conclusion, intensive therapy with ASCT is potential
interesting in the treatment of patients with FL but its role needs
to be reviewed specifically with regard to the high rate of long
term complications such as myelodysplastic syndromes and acute
leukemia estimated to ragne between 8 and 14% [62]. Moreover,
considering all the alternative ways to treat FL, three crucial
questions remain: who should receive a transplant, when and how?
Well-defined studies are necessary to define more relevant
prognostic factors and the optimal procedure of ASCT in order to
answer these questions. One such study evaluating the role of
rituximab for in vivo purging and maintenance in relapsed patients
is under way in Europe (EBMT LYM 1).
Table 2 Autologous stem cell transplantation as
first-line treatment: randomised trials
|
Author
|
Treatment
|
Patients
|
Follow-up
|
DFS (5 years)
|
OS (5 years)
|
|
Lenz et al. [58]
|
- MCP/CHOP+ IFN
- CHOP + ASCT
|
26
|
17 months
|
47%
|
NE
|
|
18
|
|
83% (p < 0.03)
|
NE
|
|
Sebban et al. [59]
|
|
209
|
56 months
|
36% (7 years)
|
74% (7 years)
|
|
192
|
|
45% NS
|
86% (p = 0.05)
|
|
Deconinck et al. [60]
|
CHVP-IFN VCAP+ASCT
|
82
|
56 months
|
37%
|
83%
|
|
66
|
|
59% (p < 0.017)
|
77.5% NS
|
Allogeneic stem cell transplantation
Several results support the existence of a graft- versus- lymphoma
effect. First, a lower risk of relapse is associated with the use
of allogeneic rather than autologous grafts. This is the case even
when conditioning regimens are similar, so that the decrease in
relapse is not clearly related to high-dose therapy alone. Evidence
of a GvL effect also comes from induction of remission after
cessation of immunosuppression or donor-leukocyte infusion (DLI) in
patients with progressive NHL following allogeneic transplantation
[63]. Moreover, in some cases, regression of the disease and the
achievement of complete remission have been noted in association
with the presence of chronic graft versus host disease [64] .There
is accumulating evidence that disease-cells can elicit T-cell
clones that are distinct from GHVD reacting T cells, thus providing
molecular proof that GVL and GVHD can be separated [65].
Van Biesen has recently published a retrospective comparison of
autologous and allogeneic hematopoietic stem cell transplantations
in 904 patients with follicular lymphoma [66]. Its conclusions are
clear: if the pattern of treatment failure after allogeneic
transplantation was markedly different from that after autologous
transplantation with a recurrence rate of only 20% after one year
and very few relapses after, outcome was, however, adversely
affected by a high early treatment-related mortality (TRM) rate of
about 40%. This is why an alternative strategy to reduce TRM has
been developed, consisting in the use a lower dose,
nonmyeloablative, preparative regimen designed not to eradicate the
lymphoma but to provide sufficient immunosuppression to achieve
engrafment, thus allowing the development of an immune GvL effect.
FL should be a good indication for these nonmyeloabaltive regimens,
as its long natural history gives the time to exploit the
potentially beneficial GvL effect. So far, few results of
nonmyeloablative allogeneic transplantations are available in FL.
Khouri et al. reported a series of 20 cases of heavily
pretreated FL [67]. Patients received fludarabine
30 mg/m2 administered intravenously (IV) daily on
day – 5 to day – 3 before transplantation, cyclophosphamide
750 mg/m2 IV daily four hours after fludarabine and
high doses of rituximab (375 mg/m2 on day – 13 and
1000 mg/m2 on day – 6, + 1, + 8). All patients
had durable engrafment with 80% donor cells one month following
transplantation. Hematopoietic recovery was prompt. The TRM was
relatively low (8%) and the cumulative incidence of acute GvH was
20%. With a median follow-up of 19 months, the current
progression- free- survival was 85 +/- 8%. Other reports have also
shown promising results [68, 69]. However, whether or not these
potential benefits can be directly translated into improved patient
survival should be evaluated in a prospective trial.
New agents
The antigen receptors expressed by FL cells, or idiotypes,
represent tumor-specific antigens. A number of trials have been
conducted on the use of idiotype-specific vaccination in the
treatment of FL. The first approach was based on purification of
native idiotype protein from cell culture supernatants. In this
strategy, lymphoma cells obtained from a node biopsy are fused to
an existing myeloma cell line to produce a hybridoma that generates
an immunoglobulin that matches the idiotype of the lymphoma.
Interesting results based on this strategy were reported by Hsu et
al. [70]. Additional research efforts focus on the most efficacious
vaccination route and on the development of convenient methods to
manufacture individual idiotype vaccines. Others new approaches
including proteasome inhibition [71] and antisense therapy [72] are
currently under investigation with early promising results.
Conclusion
The management of FL is one of the most controversial issues in
oncology. The wide spectrum of therapeutic options makes the
decision difficult. Our approach is summarized in figures 1 and 2.
Young patients with unfavourable prognostic factors are candidates
for intensive therapies such as ASCT including rituximab in
debulking chemotherapy and/or in the conditioning regimen and/or
during maintenance. Obviously, these patients should therefore be
considered candidates for investigational clinical trials.
Conversely, in young patients without poor prognostic factors,
deferred treatment is generally considered.
In the case of older patients, the decision to use any of the
standard or newer modalities is based on the presence of poor
prognostic features and the patient’s tolerance of planned therapy.
A watch-and-wait approach is appropriate in asymptomatic patients
and rituximab monotherapy seems to be a good option in this set of
patients when treatment is required. In spite of the significant
progress made with the introduction of monoclonal antibody-based
therapy, many questions remain unanswered. Therefore, clinicians
treating patients with FL should enter patients in the ongoing
phase III trials in order to define the better treatment algorithm
to alter the natural history of this disease.
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