Front-Line Treatment of Indolent Non-Hodgkin Lymphomas
Igor Aurer
Division of Hematology, Department of Internal Medicine, University Hospital Center and
Medical School, Zagreb, Croatia.
Indolent non-Hodgkin lymphomas (NHLs) are slowly growing neoplasms derived from
peripheral lymphoid cells and characterized by a prolonged clinical course [1]. Many patients
have active disease for months or even years with a good quality of life (QoL) and no or only
minimal symptoms. In Caucasians and areas of moderate climate, almost all cases are of B
cell origin. This article reviews available front-line treatment options for patients with newly
diagnosed indolent B cell NHL (B-NHL).
The adoption of Classification-Revised European-American Lymphoma (REAL) and
World Health Organization (WHO) classifications has significantly improved the ability of
hematopathologists to distinguish different types of lymphomas [2]. The most frequent types
of indolent B-NHL are follicular lymphoma (FL), small lymphocytic lymphoma (SLL),
marginal zone lymphoma (MZL), and lymphoplasmacytic lymphoma (LPL). The average age
at diagnosis is approximately 65 years. Many patients are elderly and have significant
comorbidities that affect their QoL and ability to tolerate treatment. Indolent NHLs respond
well to radiotherapy and to a variety of chemotherapeutic regimens but are incurable with
standard treatment due to a propensity for relapse, except for a small percentage of patients
presenting with localized, ie stage I disease. Generally, the course of the disease is
characterized by multiple relapses and remissions that tend to become ever shorter until the
patient finally dies of infection, NHL, or an unrelated disorder. Randomized studies have
shown that deferring treatment in patients with asymptomatic, slow-growing disease until
progression does not jeopardize their survival [3–5]. If this “watchful waiting” approach is
used, approximately 15% of patients die from unrelated causes without ever needing
lymphoma treatment. However, this method is not universally accepted, as will be discussed
later in more detail.
A variety of chemotherapy regimens has been advocated for treatment of indolent BNHLs. While more aggressive regimens usually result in higher complete remission rates and
sometimes in improved event-free survival (EFS) rates or similar [6–10], only a single trial
using intensive chemotherapy and interferon maintenance has shown a difference in overall
survival (OS) rates in favor of a certain front-line chemotherapy regimen [11]. In addition, up-
front intensification with high-dose chemotherapy with or without stem cell support does not
seem to improve OS, but significantly increases toxicity [12–15]. This is reflected in the wellknown results of long-term follow-up of patients with FL treated with different chemotherapy
regimens at Stanford University, CA, USA, which shows equivalent survival rates over a 30year period [16]. Therefore, measures other than OS rates should be used in deciding upon the
best front-line treatment for a patient with disseminated indolent NHL.
[AU: Peer review comment: “The information included is related to CHOP but many
have adopted the addition of rituximab along with most of the chemotherapy regimens used to
treat low-grade lymphomas. Therefore, you may wish to consider adding the data that is
available regarding R-CHOP along with your data on CHOP.”
Response: The disucssion above relates to chemotherapy only, not to a combination of
chemotherapy and immunotherapy. I believe that this is clear from the text, but if it isn't,
please feel free to add this statement.]
Follicular lymphoma (FL): the big guy on the block [H1]
FL is the most frequent indolent B-NHL accounting for approximately 30% of all
NHL cases [2]. FLs are divided into three grades (I, II, and III) depending on the number of
large cells (“centroblasts”) per average high-power field of a microscope. FLs are divided into
three groups (follicular, mixed, and diffuse) based on their growth pattern. While grade I and
II FLs are generally regarded as indolent and grade III FLs as aggressive, there is no
consensus on the distinction between small cells (“centrocytes”) and centroblasts making the
grading irreproducible and of doubtful clinical significance. In addition, growth pattern does
not seem to be of major clinical importance except for type IIIB. Those are grade III FLs with
a predominantly diffuse growth pattern. Their biological and clinical characteristics are
indistinguishable from diffuse large B-cell lymphoma (DLBCL) and should be regarded and
treated as such. Some patients, mostly with grade I FL, experience spontaneous remissions,
usually of short duration.
Starting treatment: “watchful waiting” versus “waiting and worrying” [H2]
Most academic hematologists, especially in Europe, advocate the concept that patients
with disseminated indolent NHL, including FL, should not be treated unless they are
symptomatic, have a rapidly growing or high tumor burden, or have signs of suppression of
normal hematopoiesis [1]. An academic minority and a somewhat larger percentage of
practicing hematologists disagree, occasionally leading to heated debates. Arguments in favor
of “watchful waiting” come from trials that have used chemotherapy that is not standard today
and have not included immunotherapy [3–5]. Therefore, it is possible to argue that treating
these patients with a more effective therapy such as R-CHOP (combination of rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone) might result in a different
outcome. An argument in favor of watchful waiting is that in most trials there was no
evidence at all of an improvement in the early treatment arm. Another argument in favor of
this strategy comes from results of long-term follow-up of FL patients from Stanford
University, which showed no improvement in results from different treatment regimens over a
period of 3 decades [16]. This would indicate that early treatment with more aggressive
chemotherapy does not improve the most important outcome measure, the OS rate.
Unfortunately, the latter argument can be a double-edged sword, because cohort studies from
other groups show an improvement in event-free survival (EFS) rates and somewhat less
pronounced, but still significant, improvement in OS rates over different treatment periods
[17].
This question can be addressed in a slightly different way, by asking whether there
could be another reason, besides an increase in the tumor mass, that delaying treatment might
be harmful. For example, are tumor cells expected to acquire mutations that will make them
less sensitive to treatment? Knowing the biology and indolent course of the disease, the
answer is most probably not. Therefore, it seems safe, prudent, and in accordance with
evidence-based medical principles to delay treatment of disseminated FL until one of the
criteria for beginning treatment is fulfilled. However, it should also be remembered that early
treatment is not detrimental and that there will be patients and physicians for whom watchful
waiting will be waiting and worrying. For these patients, early treatment might be a more
acceptable alternative.
Rituximab: the gold standard [H2]
The only drug shown to significantly improve OS rates, when used as part of a frontline treatment regimen, is rituximab. Trials comparing cyclophosphamide, vincristine, and
prednisone (CVP) with rituximab (R)-CVP; CHOP with R-CHOP; mitoxantrone,
chlorambucil, and prednisone (MCP) with R-MCP; and cyclophosphamide, doxorubicin,
etoposide, prednisone, and interferon-α (CHVP) with R-CHVP have all shown that the
addition of rituximab improves not only complete remission and EFS rates but also the rate of
OS (Table 1) [18–21]. The improvement is remarkably similar across the trials, and amounts
to approximately 2.5% per year of follow-up (that is, 2.5% at 1 year, 5% at 2 years etc.), at
least during the limited published follow-up period of about 4 years [22]. The addition of
rituximab to chemotherapy does not lead to an increase in the incidence and severity of side
effects. Therefore, rituximab should definitely be part of any front-line treatment for FL.
Choosing rituximab’s partners: “speaking softly” versus “carrying a big stick”[H2]
Should front-line rituximab treatment be given as monotherapy or in combination with
chemotherapy? In the latter case, what is the most appropriate chemotherapy regimen? What
is there to base our answers on, given that the lack of randomized clinical trials reporting
differences in OS rates? In practice, there are multiple answers to these questions. Results of
more frequently used front-line regimens are presented in Table 2. Rituximab monotherapy
with a short maintenance results in outcomes similar to those achieved with R-CVP or Rchlorambucil without maintenance [18,23,24]. Rituximab monotherapy is somewhat less toxic
but more expensive. Response rates to R-CHOP are >90%, and the EFS is 5–6 years, more
than twice that observed with R-CVP [19]. Data are emerging suggesting that fludarabinebased combinations, such as fludarabine and mitoxantrone (FM) result in even slightly better
outcomes [25]. All these treatments are generally well tolerated, with CHOP having more
hematological toxicity and fludarabine-based combinations resulting in more infectious
toxicity.
There are two opposing approaches for deciding on the optimal front-line treatment,
although various compromises between them are possible. The first approach is to start with
the mildest possible treatment regimen and then, when the patient stops responding, switch to
another, more aggressive regimen. With this approach, financially conscientious healthcare
systems most frequently choose to use R-CVP (although it might be rituximab combined with
chlorambucil and steroids), and those not limited by tight budgets tend to prefer rituximab
monotherapy. When patients stop responding, they can be switched either to R-CHOP, a
rituximab and fludarabine containing combination, such as R-FND (fludarabine, mitoxantrone,
dexamethasone) or R-FCM (fludarabine, cyclophosphamide, mitoxantrone), or to
radioimmunotherapy.
The second approach is to give the most aggressive therapy that still enables the
patient to continue with his routine daily activities. The thinking behind this is that being in
complete remission and having a long EFS are important favorable outcomes. As there are at
least two different treatment classes that are not cross-resistant, giving one of them up-front
does not jeopardize the outcome of later salvage treatment followed by an intensive
consolidation such as transplantation or radioimmunotherapy. There is financial argument in
favor of this approach which, to my knowledge, has not previously been raised. For patients
receiving R-CHOP the median time to next anti-lymphoma treatment is approximately 6 years
and in those receiving R-CVP 3.5 years [18,19]. This means that with R-CHOP there is an
average delay of second-line treatment for approximately 2.5 years. As salvage treatments
also contain rituximab, this delay results in a substantial financial gain for the healthcare
system. Of course, this argument is only valid for patients able to tolerate more aggressive
treatment without significant side effects who do not have substantial comorbidity that might
reduce their life expectancy and QoL, irrespective of the outcome of FL treatment. On the
other hand, there is a possibility that patients treated with front-line CHOP might have a
higher frequency of serious late side-effects such as cardiac failure or secondary leukemias,
than those treated with CVP. Unfortunately, there are no randomized trials comparing R-CVP
with R-CHOP to prove or disprove these arguments although one such trial is being planned
in Poland.
Regarding more aggressive protocols, essentially there is a choice between CHOP and
fludarabine-based regimens. Other treatment types (for example MCP, CHVP, or
bendamustine-containing combinations) are not widely used outside of certain cooperative
groups or geographic regions. Available data from comparative trials suggest that the
superiority of rituximab and fludarabine combinations in comparison with R-CHOP is mainly
related to increased complete remission but probably not EFS rates [25]. There is a dearth of
data on outcomes of patients receiving first a fludarabine-containing regimen and then CHOP.
Therefore, for the time being it seems safer to give CHOP first and reserve the fludarabine
regimens for later than vice-versa.
[AU: Peer review comment: “While there are those who use R-CHOP frontline in the
management of low-grade lymphomas, there are many oncologists in academic settings
who would disagree with the use of R-CHOP frontline and do not feel it should be frontline therapy in the management of low-grade lymphomas. We certainly have many
patients with follicular lymphoma who live >10 years and therefore, long term effects of
therapy must be considered. Although, I can not disagree that R-CHOP is used as frontline, it is not a panacea and you may want to consider the pros and cons of this therapy as
frontline.”]
Response: As requested, I have added a sentence (in green) related to the possible late
side-effects of CHOP.
Non-FL indolent NHL: the orphans [H1]
Small lymphocytic lymphoma (SLL), marginal zone lymphoma (MZL), and
lymphoplasmacytic lymphoma (LPL) are non-FL indolent NHLs [3]. If extranodal and
splenic MZLs are excluded, these entities are infrequent and represent approximately 10% of
all NHL cases. Before the era of rituximab treatment, their prognosis was inferior to FL, with
approximately 60% of patients remaining alive after 5 years and an average life expectancy of
6–7 years [26]. During this time and that of the widespread use of the REAL and WHO
classifications, this patient population was usually grouped with FL patients and treated
similarly [6,7]. Since the distinction between different indolent lymphoma types became more
important to researchers, many cooperative groups stopped enrolling patients with these
diseases into randomized clinical trials; therefore, it has been extremely difficult to collect
enough cases to achieve sufficient statistical power. Even in groups that continued to perform
randomized trials within the whole indolent NHL population, the number of patients with
specific non-FL types has been too small to reach statistically firm conclusions specific to that
lymphoma type [8,9,12,24,27]. For this reason, there are no solid data regarding treatment
efficacies in this patient population and little hope of finding some in the near future. Phase II
trials indicate that non-FL indolent lymphomas respond to rituximab, although possibly less
favorably than FLs [24,28–31]. This difference seems to be more pronounced in patients with
relapsed or refractory disease than in previously untreated cases [28,32]. However, indolent
non-FL lymphomas also respond less well to other treatment modalities, as evidenced by the
inferior survival rates of patients with SLL, MZL, and LPL in comparison with FL during the
pre-rituximab era [26]. Given that none of the currently available treatments specifically
targets one type of NHL only, it seems reasonable to accept the conclusions that are emerging
from Phase II trials and assume that non-FL indolent lymphomas behave similarly to FL,
albeit not quite so favorably. This means that patients with SLL, nodal MZL, and LPL should
be treated in the same way as patients with FL, that is, with watchful waiting until an
indication for treatment emerges upon which treatment with rituximab alone or in
combination with chemotherapy is advised [AU: Words added to the above sentence to
incorporate peer review comments. Is this OK? And the sentence below has been reworded]
Response: Yes, it’s perfectly OK. R-CHOP is the author’s recommendations (see FL: the big
guy on the block, pXX) except for those for whom age and comorbidity significantly reduce
the expected advantages of a more aggressive approach.
Splenic marginal zone lymphomas [H2]
Splenic marginal zone lymphomas infrequent lymphomas seem to respond less well to
chemotherapy than their nodal counterparts. Splenectomy can be a effective treatment and
improve the rate of response to other types of treatment, even in patients with disseminated
disease and a leukemic presentation [33].
Localized indolent NHL: the lucky few [H1]
Occasionally, patients with indolent NHL are identified while still in stage I.
Approximately 65% of these patients are disease free 10 years after involved-field (IF)
radiotherapy, most are cured [34–36]. Available evidence suggests that adding chemotherapy,
prior to or after radiation, does not improve OS rates [37,38]. This is not surprising in view of
the lack of effect of chemotherapy on the OS rate in disseminated disease. There are no data
on the effect of rituximab in this setting. Therefore, current evidence suggests that IF
radiotherapy is still the optimal treatment in these patients. However, there is no consensus
about the most effective dose of radiotherapy. Many radiotherapists would opt for a full 40Gy dose, although there is a trial, indicating that a reduction to 24 Gy is safe [39]. Patients
with a systemic relapse after IF irradiation seem to have an inferior prognosis than previously
untreated patients with primary disseminated disease [40].
Localized extranodal (stage IE) marginal-zone lymphomas – mucosal-associated
lymphoid tissue lymphomas: the goodies [H1]
Extranodal MZLs or mucosal-associated lymphoid tissue (MALT) lymphomas differ
from other types of NHLs in that many of them are antigen-driven and regress once the
causative antigen is eliminated. The stomach is most frequently affected and the tumor is
usually caused by chronic Helicobacter pylori infection. Controlled clinical trials have shown
that treatment directed against H. pylori leads to MALT lymphoma regression in
approximately two-thirds of cases, even if the bacteria cannot be identified in gastric biopsies
[41–43]. Another possibility is to use gastric irradiation in H. pylori-negative patients. The
addition of low-intensity chemotherapy does not improve outcomes. Localized gastric MALT
lymphoma has a very favorable prognosis, the disease-specific mortality was 0 in a
randomized trial. Therefore, even in patients who initially fail anti-H. pylori therapy,
aggressive treatment does not seem to be indicated.
Ocular adnexa are another frequent localization of MALT lymphomas. Some, but not
all studies suggest Chlamydia psittaci to be the culprit [44,45]. The observed differences
might result from variations in exposure to infectious agents in different geographical areas.
While these discrepancies are being resolved, it seems reasonable to add a course of
antibiotics (azitromycin or tetracyclines) to the treatment directed against lymphoma, at least
for patients coming from geographical areas with unknown or high C. psittaci positivity rates.
Patients with localized ocular MALT lymphomas are routinely treated with radiotherapy but
uncontrolled studies suggest that similar results can be obtained with low-intensity
chemotherapy, such as CVP or chlorambucil [46,47]. As the prognosis of these patients is
excellent, aggressive front-line treatment is not indicated.
Future directions: the crystal globe [H1]
The PRIMA (Primary Rituximab and Maintenance) trial, investigating the role of
rituximab maintenance after front-line immunochemotherapy in disseminated FL has recently
been closed for accrual. First results are expected in the second half of 2008. Most
hematologists expect results to be positive, although few would expect that the combination
of induction immunochemotherapy and rituximab maintenance to result in a cure. A
randomized trial of consolidation with radioimmunotherapy has also recently been closed;
results from the Phase II trials are encouraging [48]. The combination of these two approaches
might have a more profound effect on indolent NHL than either method alone, but this should
first be tested in later disease phases; one such trial is to begin shortly.
Other monoclonal antibodies are also under investigation for the treatment of NHL, such as
those targeting CD22 and CD80, in addition to enhanced versions of anti-CD20 [AU: this
sentence has been added to incorporate peer review comments. Is this OK?]. Response: Yes,
it’s perfectly OK. Another interesting alternative could be adding lenalidomide, or less
optimistically bortezomib, to rituximab maintenance. And while in this era of targeted therapy
cytotoxic agents seem to be old-fashioned, interesting data are emerging to suggest that
bendamustine will be a better alternative to cyclophosphamide in combination chemotherapy
regimens in the years to come [49].
Conclusion [H1]
As disseminated indolent NHLs are incurable with standard treatment, the choice of
front-line regimen for each patient must take into account factors that might influence the
need and possibilities for subsequent therapies, primarily age and comorbidity, as well as
economic factors. Rituximab is the only drug shown to increase the OS rate in this patient
population and should be part of every front-line regimen. Pending more experience with
front-line fludarabine-containing regimens, in comparison with other frequently used
therapies, indirect evidence suggests that R-CHOP may result in better EFS rates and longer
delays in time to next treatment, thus reducing total treatment costs [AU: Words have been
added to the above sentence to incorporate peer review comments. Is this OK?]. Response:
Yes, it’s perfectly OK. Unfortunately, evidence for this is only indirect. In elderly and unfit
patients in whom CHOP is expected to significantly reduce QoL or whose life expectancy
makes it unlikely that they will require multiple treatment lines, less intensive regimens, such
as R-CVP or R-chlorambucil with or without steroids, may be more useful. If, in such patients,
treatment costs are not an issue, rituximab monotherapy may result in comparable results with
even less toxicity.
Splenectomy should be considered in patients with splenic MZL in need of treatment.
Localized indolent nodal NHLs should be treated with IF radiotherapy, gastric MALT
lymphomas with treatments directed against H. pylori without the addition of chemotherapy
and ocular MALT lymphomas with radiotherapy or low-intensity chemotherapy, possibly
with the addition of antibiotics that are active against C. psittaci.
Address for correspondence: Dr Igor Aurer, Division of Hematology, University Hospital
Center Rebro, Kispaticeva 12, 10000 Zagreb, Croatia. Email: aurer@mef.hr
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Table 1. Results of randomized trials comparing chemotherapy alone with chemotherapy +
rituximab.
Reference
Regimen
n
RR
CR +
(%)
CRu
EFS / TTP
OS
(%)
[18]
[19]*
[20]**
CVP
159
57
11
median
15 mo
R-CVP
162
81
41
CHOP
205
90
17
at 2
63%
R-CHOP
223
96
20
years
82%
MCP
96
75
25
median
29
at 30 months
32 mo
85%
89%
at 2 years
90%
95%
at 4 years
74%
months
R-MCP
105
92
50
Not
87%
reached
[21]**
CHVP
175
85
49
at 30
62%
Patients alive
145
R-CHVP
184
94
76
months
78%
after median
169
follow-up 30
months
.
CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CR: complete remission;
CRu: unconfirmed complete remission; CVP: cyclophosphamide, vincristine, and prednisone;
CHVP: cyclophosphamide, doxorubicin, etoposide, prednisone, and interferon-α; EFS: eventfree survival; OS: overall survivalMCP: mitoxantrone, chlorambucil, and prednisone; Mo:
months; R: rituximab; RR: response rate; TTP: time to progression.
*
Responding patients <60 years of age were randomized between interferon maintenance and
autografting, while responding older patients received interferon maintenance.
** All responding patients received interferon maintenance
RR
includes CR, unconfirmed CRu, and partial remissions
CR
only, CRu not reported
Table 2 Results of front-line treatment in patients with disseminated follicular lymphoma
Reference
Regimen
RR (%)
CR + CRu
EFS
OS
[23]
R8
67
9%
36 months
not reported
[18]
R-CVP
81
41%
32 months
89% at 2.5
years
[19]
R-CHOP*
[25]
R-FM
96
96
25%
90%
82% at 2
95% at 2
years
years
63% at 3
94% at 3
years
years
CHOP: cyclophosphamide, doxorubicin, vincristine, and prednisone; CVP:
cyclophosphamide, vincristine, and prednisone; EFS: event-free survival; FM: fludarabine
and mitoxantrone; MCP: mitoxantrone, chlorambucil, and prednisone; OS: overall survival;
R: rituximab.
* Responding patients <60 years old were randomized between interferon maintenance and
autografting, while responding older patients received interferon maintenance.
RR
includes CR, unconfirmed CRu, and partial remissions
CR
only, CRu not reported