Hematological Oncology

Hematol Oncol 2015; 33: 129135

Published online 22 July 2014 in Wiley Online Library
(wileyonlinelibrary.com) DOI: 10.1002/hon.2154

Original Research Article

Chlorambucilrituximab as first-line therapy in patients

affected by follicular non-Hodgkins lymphoma: a
retrospective single-centre study
Giovanni Martinelli1, Juan Montoro1*, Anna Vanazzi1, Giovanna Andreola1, Sarah Liptrott1, Davide Radice2,
Mara Negri1, Lorenzo Preda3, Giancarlo Pruneri4 and Daniele Laszlo1
1

Division
Division
3
Division
4
Division
2

of Clinical Hemato-oncology, European Institute of Oncology, Milan, Italy

of Epidemiology and Biostatistics, European Institute of Oncology, Milan, Italy
of Radiology, European Institute of Oncology, Milan, Italy
of Pathology, European Institute of Oncology, Milan, Italy

*Correspondence to: Juan

Montoro, Hemato-oncology
Division, European Institute of
Oncology, Via Ripamonti 435,
20141 Milan, Italy.
E-mail: juanmontorogomez@
hotmail.com

Received 5 February 2014

Revised 30 April 2014
Accepted 25 June 2014

Abstract
Rituximab, a chimeric monoclonal antibody directed against the CD20 antigen, has been
shown to be active in newly diagnosed and relapsed patients with follicular lymphoma
(FL), both as monotherapy and in combination with chemotherapy. Many studies suggest
that the prognosis of patients with FL may improve when it is used in combination with
chemotherapy. Despite these advances, the disease remains essentially incurable with
standard therapy, and novel approaches to treatment are needed because optimal therapy
is not dened. The combination of chlorambucilrituximab is one of several standard
treatment options for FL. Here, we considered data arising from 75 patients with newly
diagnosed FL at the European Institute of Oncology treated with the combination of
rituximab plus chlorambucil. The aim of this study was to evaluate the efcacy and safety
of chlorambucil and rituximab, delivered 6 mg/m2/day orally for 6 weeks and 375 mg/m2 in
a standard 4-weekly schedule, respectively. Patients responding to the induction therapy
received a prolonged therapy with four additional cycles of chlorambucil plus rituximab.
Seventy-one patients (94.6%) completed the treatment; four patients discontinued treatment because of grade 34 hematological toxicity. The overall response rate was 97.3%
including 74.7% of complete responses. Only two patients had a stable disease at revaluation after treatment. With a median follow-up of 57 months, 72 patients (96%) are alive.
Median event-free survival (EFS) and median overall survival (OS) were not reached;
5-year OS rate was 98.4%. The 5-year EFS was 71.3%. By univariate and multivariate
analyses, elevated beta-2 microglobulin levels and partial responses to therapy were
correlated with worse EFS. These results suggest that the combination of chlorambucil
and rituximab is an active and safe regimen in patients with newly diagnosed FL,
principally in those with low tumour burden and favourable prognostic factors.
Copyright 2014 John Wiley & Sons, Ltd.
Keywords: follicular lymphoma; rituximab; chlorambucil; toxicity; clinical outcome

Introduction
Follicular lymphomas (FL) are a subtype of B-cell nonHodgkins lymphoma (NHL) characterized by clinical
behaviour of continuous remissions and relapses. It is the
second most common type of lymphoma in Western countries, representing between 22% and 40% of NHL in the
World Health Organization classication [1,2].
Management of indolent NHL still remains controversial
at the present time. In spite of signicant improvements
after the introduction of monoclonal antibodies and its

Copyright 2014 John Wiley & Sons, Ltd.

combination in different treatment strategies, the prognosis

of FL has practically remained unchanged with median
survival ranging from 6 to 10 years [3,4].
Monoclonal antibody anti-CD20 (rituximab) delivered
alone has been demonstrated to be a valid treatment option
either in relapsing or in newly diagnosed follicular NHL
patients. Prolonged exposure to rituximab with different
schedules improves clinical results, at least in terms of
response rate and event-free survival (EFS), rather than
those achieved with a standard weekly schedule. Prolonged
treatment with rituximab does not induce additional

G Martinelli et al.

130

toxicity and may induce long-term remission [58]. In

addition, preliminary results reported in a clinical trial
comparing a watch-and-wait approach versus rituximab
induction therapy versus rituximab induction followed by
maintenance have demonstrated better progression-free
survival in patients receiving induction and maintenance
with rituximab, without additional toxicity [9].
However, in patients requiring treatment, chemotherapy
in combination with rituximab is the most widely considered
option, but there is no consensus on which chemotherapy
regimen must be used with rituximab and for which patient
characteristics [1013]. It is well known that whichever
therapy is used, the disease will surely relapse. Thus, in the
management of follicular NHL patients, many prefer to
privilege their quality of life with a less intensive treatment
approach and lower toxicity.
We previously demonstrated the feasibility and efcacy
of chlorambucil plus rituximab combination therapy in the
treatment of newly diagnosed or relapsed/refractory indolent B cell including follicular NHL patients [14,15]. Here,
we report our extended retrospectively collected data
regarding the combination of chlorambucil plus rituximab
in newly diagnosed follicular NHL patients not included
in the previous report, with the aim to conrm the safety
and the efcacy of this combination and to evaluate its
impact on the toxicity, overall response rate (ORR), EFS,
and overall survival (OS).

Patients and methods

Patient characteristics
We analysed data from 75 newly diagnosed patients with
FL who were treated at the European Institute of Oncology
between November 2001 and January 2005 and from
September 2007 to November 2010 (the reason for this
gap is due to the enrolment of patients in a concomitant
clinical trialSAKK 35/03). A written consent to treatment and use of biological samples was obtained prior to
start treatment. All patients with histologically proven FL

(grade 1, 2, or 3a) according to the World Health Organization classication [1] or with any Ann Arbor stage requiring systemic therapy were considered for the present
study. The requirement for therapeutic intervention was
dened by the presence of at least any one of the following
criteria: presence of B symptoms (night sweats, fever, or
weight loss), bulky disease (mediastinal lymphomas greater
than 7.5 cm or other lymphomas greater than 5 cm in maximal diameter), impairment of normal haematopoiesis with
haemoglobin levels less than 100 g/L, granulocyte count less
than 1.5 109/L, thrombocyte count less than 100 109/L, or
a rapidly progressive disease.
Clinical, laboratory, imaging, and follow-up data were
obtained from medical notes. Such data were used to assess
patient and disease characteristics, response to therapy,
disease progression, toxicity, and survival.

Treatment
The planned schedule is shown in Figure 1. Treatment
consisted of oral chlorambucil (Leukeran) 6 mg/m2/day
administered daily for six consecutive weeks in association
with standard 4-weekly rituximab (375 mg/m2 i.v.) administration schedule.
Eight weeks later, patients were clinically evaluated, and
those who achieved a clinical response or had a stable disease
received a prolonged therapy with chlorambucil 6 mg/m2/day
for 2 weeks every month (four cycles) plus rituximab
(375 mg/m2 i.v.) monthly. Two months after the treatment, a
clinical and laboratory re-evaluation was conducted. Oral
chlorambucil was administered according to a standard schedule [16], which has been shown to be safe and feasible
[14,15]. If grade 3 and 4 hematological toxicity, according
to the National Cancer Institute toxicity criteria, was observed
during the induction phase or prolonged treatment phase, then
the chlorambucil dose was reduced by 33% or discontinued.
Chlorambucil was delayed if the hematological toxicity of
the previous course had not completely resolved. Treatment
was denitively discontinued if prolonged severe hematological toxicity was observed. Haematopoietic growth factors

Figure 1. Chlorambucil and rituximab schedule

Copyright 2014 John Wiley & Sons, Ltd.

Hematol Oncol 2015; 33: 129135

DOI: 10.1002/hon

Chlorambucilrituximab in patients with follicular NHL

were not routinely administered, and no specic recommendations were made regarding antimicrobial prophylaxis.

131

Table 1. Baseline patient characteristics (n = 75)

Number Missing
(%)
values (%)

Characteristic

Evaluation of response and follow-up

Sex

Evaluation of response was performed within 2 weeks after

the end of induction therapy and then 2 months after the
end of prolonged therapy. Response was dened according
to the International Working Group criteria [17]. All patients were assessed for toxicity according to the National
Cancer Institute Common Toxicity Criteria, version 2.0
(http://ctep.cancer.gov/protocolDevelopment/electronic_
applications/docs/ctcv20_4-30-992.pdf) and for clinical
response. Laboratory studies, including complete blood
count and routine serum chemical analyses, were performed weekly during induction therapy and monthly
during the prolonged therapy programme.

Age > 60 years

Histological grade
Ann Arbor stage

Lactate dehydrogenase >

normal
Haemoglobin < 12 g/dL
2-microglobulin > 3 mg/
dL
Bulky disease
Bone marrow inltration

Statistics
Extranodal sites

Patients characteristics at study entry, duration of therapy,

and response to therapy [complete remission (CR), partial
remission (PR), and stable disease] have been summarized
as count and percentage (categorical variables), median,
and min and max (continuous variables). The ORR was
dened as the sum of CR and PR rates. OS and EFS were
dened as the time between the date of the treatment start
and the date of death for any cause or progression, respectively. Median OS and EFS were estimated by the
KaplanMeier method and tabulated with 95% condence
intervals (CI).
KaplanMeier curves were compared by the log-rank
test. Unadjusted and adjusted hazard ratios (HR) were
estimated by the Cox regression model. Groups of patients
identied by the levels of the prognostic factors were compared using either the chi-square or Fishers exact test as
appropriate. All tests were two tailed and considered statistically signicant at the 5% level. Statistical analyses were
conducted with SAS 9.2 (SAS Institute Inc., Cary, NC).

Results
The clinical characteristics of 75 patients are provided
in Table 1. The cohort median age was 58 years (range,
3080), with 33 men and 42 women. Patients were
diagnosed with grade 1 (28%), 2 (61.3%), or 3a (10.7%)
FL. The majority of patients (73%) had advanced-stage
disease at diagnosis (Ann Arbor stage > II) and a low prognostic index according to the Follicular Lymphoma International Prognostic Index (FLIPI) score. Thirty-nine patients
(52%) were considered to be in the low-risk category (zero
to one factor), 20 (26.7%) in the intermediate-risk category
(two factors), and 10 (13.3%) in the high-risk category
Copyright 2014 John Wiley & Sons, Ltd.

Presence of B symptoms
Follicular Lymphoma
International Prognostic
Index score

33 (44.0)

42 (56.0)
32 (42.7)

1
21 (28.0)

2
46 (61.3)
3a
8 (10.7)
I
5 (6.7)

II
15 (20.0)
III
24 (32.0)
IV
31 (41.3)
Yes
9 (12.0) 6 (8.0)
No
60 (80.0)
Yes
5 (6.7)

No
70 (93.3)
Yes
8 (10.7) 17 (22.7)
No
50 (66.7)
Yes
25 (33.3) 4 (5.3)
No
46 (61.3)
Yes
25 (33.3) 4 (5.3)
No
46 (61.3)
Yes
21 (28.0)

No
54 (72.0)
Yes
12 (16.0) 1 (1.3)
No
62 (82.7)
Low (01)
39 (52)
6 (8.0)
Intermediate (2) 20 (26.7)
High (35)
10 (13.3)
Male
Female

(three factors or more). Six patients could not be classied

because of lack of data. The median time from diagnosis to
the beginning of therapy was 2 months (range, 083).
Seventy-one patients (94.6%) completed the planned
treatment programme and were fully evaluated for toxicity
and response: four patients discontinued chlorambucil
because of National Cancer Institute (NCI) grade 3/4 neutropenia despite dose reduction. These patients completed the
treatment receiving rituximab alone. Reversible grade 1 to 2
events occurred in 17 patients (22.7%) during the rst rituximab infusion (chills, fever, rash, hypotension, and pruritus).
All patients except one completed induction therapy without
any delay or dose reduction. Of these, three (4%) had a
chlorambucil dose reduction during the prolonged phase of
therapy: two patients owing to grade 3/4 neutropenia and
one patient owing to grade 3 hepatotoxicity. In the latter case,
chlorambucil administration was delayed and reintroduced at
a reduced dose after normalization of liver function tests.
The most frequent hematological toxicity observed was
mild neutropenia, occurring in 15 patients (20%). No
patients required blood transfusion support: nine patients
required empirical growth factors because of grade 3/4
neutropenia. Grade 1 to 2 gastrointestinal toxicity (nausea,
gastric pain, and vomiting) and asthenia were the most
relevant non-hematological side effects experienced during
treatment, occurring in 18 (24%) and 10 (13.3%) patients,
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G Martinelli et al.

132

respectively. Two patients experienced febrile neutropenia

grade 3/4, requiring hospitalization. In both, the dose of
chlorambucil was reduced in the subsequent consolidation
phase. No toxic death was reported, and no secondary
hematological neoplasia was recorded.
After the end of induction treatment, CR was documented in 14 patients (18.7%) and PR in 59 (78.7%).
When prolonged phase therapy was completed, 42 patients
(71.2%) considered in PR after the induction phase evaluation achieved CR. The ORR in the 75 patients evaluable
for response at the end of the treatment was 97.3%, with
56 patients (74.7%) achieving a CR and 17 (22.7%) a
PR. Two patients (2.7%) had stable disease, whereas
nobody experienced disease progression.
With a median follow-up of 57 months, 14/56 CR
patients presented with disease relapse, and the OS was
98.4% at 5 years. We observed three deaths. One death
was due to relapsed disease in a 75-year-old patient, occurring 2 years after the end of rituximabchlorambucil treatment, who developed resistant and refractory disease after
several subsequent lines of combination treatment. One
patient aged 37 years died as a result of a clinical complication during a surgical intervention for a central nervous
system haemangioma. The last patient aged 50 years died
as a result of progression of an ovarian cancer, which
was diagnosed 7 years after the end of treatment with
rituximabchlorambucil.

After median follow-up of 57 months, the median OS

and EFS have not been reached, and the 5-year OS and
EFS were 98.4% and 71.3%, respectively.
In univariate analysis, beta-2 microglobulin within
normal limits (0.973.0 mg/L) and complete clinical
response to treatment were signicantly associated with
better EFS (p = 0.008 and 0.004, respectively), and the
unadjusted HR for partial-response patients was 3.54
(95% CI [1.44, 8.74]). Patients with elevated beta-2
microglobulin levels had a 3.66 times higher risk (95%
CI [1.31, 10.2]) of progress with respect to patients with
normal levels (Table 2). Multivariate analysis conrms
the results of the univariate analysis with a signicant
increased risk for progression or death with partial clinical
response and elevated beta-2 microglobulin (HR = 4.23,
95% CI [1.54, 11.6], and HR = 4.65, 95% CI [1.59, 13.6],
respectively; Table 3).

Discussion
The introduction of anti-CD20 monoclonal antibody in the
treatment of malignant lymphoma has dramatically
changed the outcomes of patients, including those with
FL [18,19]. The combination of rituximab with chemotherapy has become the standard treatment approach in both
newly diagnosed and relapsed settings [20,21]. However,

Table 2. Univariate analysis of overall survival and event-free survival (months) by levels of prognostic factors
Median (95% CI)

Unadjusted HR (95% CI)

Events/number patients

p-value

Overall survival
Event-free survival
Sex
Male
Female

Not reached
Not reached

3/75
23/75

Not reached
113.4 (71.1, )

Ref
1.67 (0.71, 3.94)

8/33
15/42

0.238

Response to therapy
Complete remission
Partial remission

Not reached
39.5 (18.4, )

Ref
3.54 (1.44, 8.74)

13/56
8/17

0.004

Not reached
Not reached

Ref
0.70 (0.30, 1.63)

13/46
9/25

0.401

Extranodal status
No
Yes

Not reached
94.4 (31.5, )

Ref
1.50 (0.63, 3.57)

15/54
8/21

0.351

2 levels
Low
High

Not reached
39.9 (10.2, )

Ref
3.66 (1.31, 10.2)

14/50
5/8

0.008

4/9
8/30
5/20
4/6
2/4

0.417

Bulky disease
No
Yes

Follicular Lymphoma International Prognostic Index score

0
Not reached
1
Not reached
2
Not reached
3
48.8 (14.6, )
4
113.4 (39.9, )

Ref
0.66 (0.20,
0.63 (0.17,
1.90 (0.47,
0.92 (0.17,

2.19)
2.35)
7.62)
5.06)

HR, hazard ratio; Ref, reference category; CI, condence interval.

Bold values reaching statistical signicance (P-value<0.05).
Copyright 2014 John Wiley & Sons, Ltd.

Hematol Oncol 2015; 33: 129135

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Chlorambucilrituximab in patients with follicular NHL

Table 3. Multivariable risk estimates (hazard ratio) for

progression or death for any cause
Adjusted hazard ratio
(95% condence interval)

Response to therapy
Complete remission
Partial remission
2 levels
Low
High

p-value

Ref
4.23 (1.54, 11.6)

0.005

Ref
4.65 (1.59, 13.6)

0.005

Ref, reference category.

Bold values reaching statistical signicance (P-value<0.05).

no chemotherapy regimen for rst-line therapy in FL patients

has been clearly established as a standard regimen [22], a
nding supported by several randomized, multicentre trials
[1013,23]. More recently, clinical results of a randomized
trial comparing three different chemotherapy regimens in
combination with rituximab have demonstrated similar results in terms of ORR, suggesting that the addition of rituximab may eliminate the differences previously observed
using the same chemotherapy regimens without monoclonal
antibodies [24].
In the present study, we present clinical results achieved
using our innovative combination, delivering a relatively
new drug (rituximab) with an old drug (chlorambucil).
Chlorambucil in the past was used alone or in combination
with prednisone or interferon-alpha 2b, becoming a valid
option in the treatment of follicular NHL patients, demonstrating a signicant response rate in either newly diagnosed
or relapsed/refractory patients with low toxicity prole
[25,26]. However, the complete response rates observed
using chlorambucil alone are in general considered lower
than those observed with other combination chemotherapies
and may justify the shorter EFS reported using such
chemotherapy approaches. Results in the current study
clearly conrm preliminary results previously reported using
chlorambucil and rituximab in patients with indolent malignant lymphoma [14]. There are now several studies that have
reported results for the combination of chlorambucil and
rituximab using a similar schedule. However, clinical results
are not comparable with those observed, as these experiences
where in different subtypes of low-grade lymphoma [27,28].
The high rate of ORR observed in the patients considered for this study could be related to the possible
synergistic effect of the combination or the relatively
favourable International Prognostic Index score of our
patients. Of relevance is the important rate of CR observed
(75%) at the end of the entire treatment; more than 70% of
patients achieving only PR after induction phase were
improved to CR at the end of the entire therapy, so that
the prolonged exposure to the combination conrms the
improvement of clinical results achieved after initial
standard weakly treatment. Rituximabchlorambucil is a
Copyright 2014 John Wiley & Sons, Ltd.

133

well-tolerated regimen, with the exception of some mild

to moderate infusion-related reactions related to rituximab
administration. Only few patients experienced grade 3 or
4 hematological toxicity. The majority of patients (95%)
completed the planned treatment, and among them, only
one patient developed prolonged neutropenia requiring
the discontinuation of chlorambucil. To date, no toxic
death and/or secondary hematological malignancies were
observed.
More than two-thirds of patients achieving CR are still
alive and free of disease with approximately 5 years of
median follow-up, suggesting that the addition of rituximab
to chlorambucil may induce a substantial and prolonged
remission. Clinical results observed in our study are very
similar to those reported with more aggressive combination
chemotherapies. However, it is impossible to compare our
results with those reported in other studies that use different
chemotherapy regimens: thus, the PRIMA study and French
experience in FL are randomized trial prospective studies
and included only patients with advanced disease (III or
IV) and/or higher FLIPI scores. Thus, the different characteristics of patients in our experience may justify the high
response rate reported in the present study.
The majority of our patients (59/75) had a low/
intermediate FLIPI score and beta-2 microglobulin within
normal limits at study entry, and approximately one-third
presents intermediate early stage. It is well known that
patients with a low FLIPI score (1 or 2) or in early stage
present with low tumour burden and consequently have a
higher probability of achieving a CR and prolonged EFS
[29]. The inclusion in the present study of patients with
FL grade 3a is of relevance. Usually, those patients were
considered as poor prognosis, justifying more aggressive
chemotherapies. However, it is still controversial whether
FL grade 3a clinically behaves more aggressively than
grades 1 and 2 and if they could therefore benet from
different therapeutic approaches. Recently, Federico et al.
observed that histological grade 3a in FL has no prognosis
impact compared with 12 in patients treated with
rituximab-containing regimens [30].
The prognostic value of beta-2 microglobulin is not well
dened and not incorporated in the FLIPI index; on the
other hand, Federico et al. [31] more recently suggest a
possible correlation between beta-2 microglobulin levels
and tumour burden. However, in our study, a possible
correlation was observed between EFS and serum beta-2
microglobulin value, which could be the explanation for
the clinical results seen (Figure 2). We thus suggest that
beta-2 microglobulin might be included in future prognostic studies of FL patients treated with combination chemotherapy and anti-CD20 agents.
In conclusion, our study shows that the combination of
chlorambucil with rituximab is a well-tolerated and active
regimen that may be considered as a possible optimal
regimen for the treatment of previously untreated patients
Hematol Oncol 2015; 33: 129135
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134

Figure 2. Event-free survival curves by 2-microglobulin levels.

KaplanMeier event-free survival curves showing the higher risk
from progression or death for patients with elevated 2-microglobulin levels

with follicular NHL, principally for patients not suitable

for more aggressive chemotherapy and with low tumour
burden but requiring combination therapy.

Conf lict of interest

The authors declare no competing nancial interests.

Acknowledgement
Juan Montoro was supported by a grant from the European Institute of Oncology Foundation.

Author contributions
G. M. and J. M. designed the study, analysed and discussed
the data, and wrote the manuscript; A. V., G. A., and D. L.
provided patient care; M. N. collected the data; S. L. edited
and reviewed the manuscript; L. P. and G. P. reviewed
biological data; D. R. assisted with the statistical analysis.
All authors approved the paper.

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DOI: 10.1002/hon