125

Outcomes in Patients With Splenic Marginal Zone

Lymphoma and Marginal Zone Lymphoma Treated
With Rituximab With or Without Chemotherapy or
Chemotherapy Alone

Apostolia M. Tsimberidou, M.D., Ph.D.1 BACKGROUND. The optimal management of patients with splenic marginal zone
Daniel Catovsky, M.D.2 lymphoma/marginal zone lymphoma (SMZL) is controversial. The objective of this
Ellen Schlette, M.D.3 retrospective study was to compare the outcomes of patients with SMZL who
Susan O’Brien, M.D.1 received treatment with rituximab, rituximab plus chemotherapy, or chemother-
William G. Wierda, M.D., Ph.D.1 apy alone.
Hagop Kantarjian, M.D.1 METHODS. The Leukemia Service database was searched for patients with splenic
Guillermo Garcia-Manero, M.D.1 lymphoma who were registered between May 1995 and October 2004. The indica-
Sijin Wen, M.S.4 tions for treatment were the same as those used for patients with chronic lympho-
Kim-Anh Do, Ph.D.4 cytic leukemia.
Susan Lerner, M.S.1 RESULTS. SMZL was confirmed in 70 patients. The median age was 64 years. The
Michael J. Keating, M.B., B.S.1 median number of CD20 molecules per cell was 69 ⫻ 103. Forty-three patients
required systemic therapy; rituximab in 26 patients, chemotherapy plus rituximab
1
Department of Leukemia, The University of Texas in 6 patients, and chemotherapy alone in 11 patients. Ten additional patients
M. D. Anderson Cancer Center, Houston, Texas. underwent splenectomy, and 17 patients were in the observation group. The
2
Institute of Cancer Research, London, United overall response rates were 88% with rituximab, 83% with rituximab plus chemo-
Kingdom therapy, and 55% with chemotherapy alone; the 3-year survival rates were 95%,
3 100%, and 55%, respectively. The 3-year failure-free survival (FFS) rates were 86%,
Department of Pathology, The University of Texas
M. D. Anderson Cancer Center, Houston, Texas. 100%, and 45% in the rituximab, rituximab plus chemotherapy, and chemotherapy
4
alone groups, respectively. Rituximab treatments resulted in longer survival and
Department of Biostatistics, The University of
FFS compared with chemotherapy. Rituximab alone resulted in disappearance of
Texas M. D. Anderson Cancer Center, Houston,
Texas. splenomegaly in 92% of patients and normalization of absolute lymphocyte
counts. In univariate analysis, younger age and rituximab-based therapy were
predictive of longer FFS.
CONCLUSIONS. Rituximab with or without chemotherapy was found to have major
Dr. Keating was a consultant and a member of the
Speakers Bureau for Berlex Laboratories, Inc., and activity in patients with SMZL. These results may be associated with high levels of
Genentech. cellular CD20 antigen sites. Rituximab should be the treatment of choice, at least
in older patients with SMZL who have comorbid diseases. Cancer 2006;107:
Dr. O’Brien was a consultant for Berlex Laborato- 125–35. © 2006 American Cancer Society.
ries, Inc., and Genentech.

Dr. Wierda has performed contract work for Berlex KEYWORDS: splenic marginal zone lymphoma, lymphoma, splenic, rituximab,
Laboratories, Inc., and X-cyte Therapies, Inc. splenectomy.

Address for reprints: Apostolia-Maria Tsimberi-

dou, MD, PhD, Department of Leukemia, Unit
428, The University of Texas, M. D. Anderson
Cancer Center, 1515 Holcombe Boulevard, Hous-
S plenic marginal zone lymphoma (SMZL) with or without villous
lymphocytes is a disorder that recently was recognized as a dis-
tinct pathologic entity in the World Health Organization classifica-
ton, TX 77030; Fax: (713) 794-4297; E-mail:
tion.1 SMZL is a B-cell neoplasm that comprises ⬍1% of lymphoid
atsimber@mdanderson.org
malignancies, although it may account for most of the otherwise
Received October 31, 2005; revision received Jan- unclassifiable chronic lymphoid leukemias that are negative for CD5.2
uary 16, 2006; accepted February 2, 2006. It was described first in 1987 as splenic B-cell lymphoma with circu-

© 2006 American Cancer Society

DOI 10.1002/cncr.21931
Published online 12 May 2006 in Wiley InterScience (www.interscience.wiley.com).

126 CANCER July 1, 2006 / Volume 107 / Number 1
lating “villous” lymphocytes (SLVL).3 SLVL is indistin-
guishable histologically from SMZL, and it is believed
that the 2 entities represent different phases of the
same process in the spleen and the bone marrow.4,5
The term “marginal zone B-cell lymphoma” (MZL)
describes mucosa-associated lymphoid tissue lym-
phoma and nodal marginal zone B-cell lymphoma.6
The optimal treatment for SMZL has not been
defined. In previous years, splenectomy was consid-
ered the treatment of choice for SMZL. The “watch-
and-wait” approach commonly is preferred in asymp-
tomatic patients with no immediately threatening
disease. However, guidelines for deferring therapy
have not been defined as they have been for chronic
lymphocytic leukemia (CLL),7 and this choice usually
is made for older patients who have disease with a
slow natural history. Although SMZLs are considered
“indolent” lymphomas, approximately 50% of deaths
from SMZL are caused by progressive disease.8 –13
More recently, numerous treatment strategies
have become available for patients with B-cell lym-
phomas. The nucleoside analogs fludarabine and pen-
tostatin and the chimeric anti-CD20 monoclonal an-
tibody rituximab have demonstrated significant
antitumor activity as single agents.14 –19 Clinical trials
have incorporated rituximab into combination che-
motherapy regimens, and results suggest that the ad-
dition of rituximab improves response rates and pro-
longs survival in patients with non-Hodgkin
lymphoma.20 –22 The combination of fludarabine, mi-
toxantrone, dexamethasone, and rituximab (R-FMD)
has significant activity in indolent lymphoma,23 and
the combination of fludarabine, cyclophosphamide,
and rituximab (FCR) also is effective in CLL.24 The
objective of this retrospective study was to compare
the complete remission (CR), failure-free survival
(FFS), and overall survival (OS) rates in patients with
SMZL who were treated with rituximab, chemother-
apy plus rituximab, or chemotherapy alone.
MATERIALS AND METHODS
A database that included all untreated and treated
patients with chronic lymphoproliferative disorders
who were referred to the Leukemia Service was
searched for patients with splenic lymphoma who
were registered between May 1995 and October 2004.
Patients were assessed prior to their first treatment at
The University of Texas M. D. Anderson Cancer Cen-
ter.
Available pathology slides were reviewed by 2 he-
matopathologists to confirm the diagnosis of SMZL/
MZL. All records were reviewed to determine clinical,
laboratory, and pathologic features at presentation in
addition to disease stage, treatment, and outcome.
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Staging evaluations at the time of presentation in-
cluded complete physical examinations, bone marrow
aspirates and biopsies, spleen or lymph node biopsies,
chest radiography, and computed tomography scans
of the chest, abdomen, and pelvis.
In the current study, at least 2 of the following
criteria had to be met to make the diagnosis of SMZL:
immunophenotype with a “CLL score” ⱕ2,25 any de-
gree of splenomegaly, a nodular/interstitial or diffuse
pattern and/or an intrasinusoidal pattern in the bone
marrow biopsy sample, spleen histology typical of
SMZL, and exclusion of CLL follicular lymphoma or
mantle cell lymphoma in the examination of periph-
eral blood and/or bone marrow. Staging and treat-
ment were determined after review of all clinical, lab-
oratory, and pathologic data in a multidisciplinary
conference. Standard or investigational treatment was
administered either at our center or in the community
by collaborating physicians. The evaluation of re-
sponse for all patients who were included in the study
was performed at M. D. Anderson Cancer Center.
Signed informed consent was obtained before all pro-
cedures and before all experimental therapy, as re-
quired by the Institutional Review Board.
The indications for therapeutic intervention in pa-
tients with SLVL/SMZL were similar to those for pa-
tients with CLL/SLL. Rituximab (Rituxan; Genentech,
Inc., San Francisco, CA) was given at standard doses
intravenously every week for 4 weeks or 8 weeks. FCR
or R-FMD was given as described previously.23,24 The
chemotherapy group was composed of patients who
received other cytotoxic agents, not including ritux-
imab or alemtuzumab therapy.
Immunophenotypic Analysis
Flow cytometric immunophenotypic studies were per-
formed on bone marrow or peripheral blood. An im-
munophenotype score was generated by using the
system described by Matutes et al.25 Assessment of the
quantitative expression of CD20 molecules on the cell
surface was performed as described previously.26
Endpoints and Statistical Methods
CR was defined as the complete disappearance of all
detectable clinical and radiographic evidence of dis-
ease, the disappearance of all disease-related symp-
toms, and normalization of biochemical abnormalities
that definitely were attributable to lymphoma for at
least 1 month. Unconfirmed CR (CRu) included pa-
tients with minimal stable radiographic changes or
with persistent lymphoid aggregates in the bone mar-
row without atypia. Partial remission (PR) was defined
as a reduction ⱖ50% in the sum of the products of the
greatest dimensions of bidimensionally measurable
 10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Rituximab for Splenic Marginal Zone Lymphoma/Tsimberidou et al. 127

disease.27 Any lesser response was considered a fail- TABLE 1

ure. The response and endpoint assessments con- Presenting Characteristics of 70 Patients with Splenic Marginal Zone
Lymphoma/Marginal Zone Lymphoma
formed to published International Workshop response
criteria.27 Survival was measured from the start of the Parameter Median Range
first treatment at M. D. Anderson or from observation
for patients in the “watch-and-wait” group to death Age, y 64 33-88
from any cause or last follow-up. Treatment failure Lactate dehydrogenase (IU/L)* 568 334-1861
␤2-microglobulin (mg/dL) 3.6 2-10
was defined as progression, recurrence, or death. FFS
Hemoglobin (g/dL) 12.0 8-16
was defined as the time from the start of the first Platelets (⫻ 109/L) 161 1-498
treatment or observation until progression, recur- Absolute lymphocyte count (⫻ 109/L) 12.1 0.2-164
rence, or death. Bone marrow cellularity (%) 40 15-100
The Wilcoxon signed rank test was used for com- Bone marrow lymphocytes (%) 47 5-82
Spleen size (cm below costal margin)† 4 0-20
parison of the paired data (before therapy vs. after
Bone marrow CD20 (%)‡ 78 1-97
therapy) for continuous variables. The Wilcoxon rank CD20 molecules/cell (⫻ 103) 69 16-260
sum test was used to examine the difference between
2 groups of patients for continuous variables. Survival * The upper limit of normal for lactate dehydrogenase at M. D. Anderson Cancer Center is 618 IU/L.
curves were estimated using the Kaplan–Meier † Forty-seven patients (67%) had an enlarged spleen.
‡ Sixty-one of 64 patients (95%) had CD20 levels ⬎20% in their bone marrow by immunophenotype.
method. The 2-sided log-rank test was used to test the
association between variables and survival or FFS. A
multivariate Cox proportional hazards regression TABLE 2
model was fit to examine the impact of risk factors on Immunophenotyping in Bone Marrow
FFS after adjusting for other factors. P values ⬍.05
Parameter No. of Patients %
were considered statistically significant. Statistical
analyses were performed using SAS software (version CD5⫹ 18/69 26
8.2; SAS Institute, Cary, NC) and S-Plus software (ver- CD23⫹ 29/61 48
sion 2000; Insightful Corp., Seattle, WA). FMC7- 8/61 13
CD22- or CD22⫹/- 8/55 15
Surface immunoglobulin weak expression 7/58 12
RESULTS
Demographics CLL score*
0-2 66 94
In total, 93 patients were registered in the database
with a diagnosis of SMZL. After review of the available ⫹: positive; -: negative; CLL: chronic lymphocytic leukemia.
pathology slides, the diagnosis was confirmed in 70 * See Matutes et al.25
patients. Twenty-three patients were excluded from
the study for the following reasons. Eighteen patients
had CLL, 2 patients had mantle cell lymphoma, and 3
immunophenotyping in bone marrow and the CLL
patients did not have slides available for review be-
scores and their components. The bone marrow infil-
cause they were returned to their referring physician.
tration pattern was interstitial in 34% of patients, nod-
The clinical and laboratory characteristics of the
ular and interstitial in 24% of patients, nodular in 20%,
70 patients at the time they received their first treat-
ment at M. D. Anderson are summarized in Table 1. diffuse and interstitial in 12%, diffuse in 6%, nodular
Forty patients (57%) were age ⬎ 60 years. There were and diffuse in 2%, and nodular, interstitial, and diffuse
39 men and 31 women. Two patients (3%) had a in 2% of patients. The median number of CD20 was
Zubrod performance status ⬎1. Fifteen patients (22%) 69 ⫻ 103 molecules per cell (range, 16-260 ⫻ 103 mol-
had Rai stage 0 or 1 disease, 22 patients (32%) had Rai ecules per cell). These results were compared with the
stage 2 disease, and 32 patients (46%) had Rai stage 3 results from patients with CLL/SLL, in which the me-
or 4 disease. Forty-seven patients (67%) had spleno- dian number of CD20 molecules per cell was
megaly. Sixty-seven patients had SMZL, and 3 patients 11.5 ⫻ 103 molecules per cell and ranged from
had predominantly nodal MZL with concurrent bone 0.6 ⫻ 103 molecules per cell to 148 ⫻ 103 molecules
marrow involvement. per cell. A significantly greater number of CD20 mol-
Fifty-nine patients (84%) had absolute lympho- ecules per cell was observed in patients with SMZL
cyte counts ⬎5 ⫻ 109/L. Twenty of 33 patients (61%) (P⬍.0001; Wilcoxon rank sum test).
who were evaluated had monoclonal gammopathy Seven patients (10%) had a history of hepatitis B (3
(immunoglobulin G [IgG], 6 patients; IgA, 2 patients; patients), hepatitis C (2 patients), or both (2 patients).
and IgM, 12 patients). Table 2 shows the results of One of 2 patients who had both hepatitis B and C also
 10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
128 CANCER July 1, 2006 / Volume 107 / Number 1

TABLE 3
Pretreatment Characteristics in 70 Patients with Splenic Marginal Zone Lymphoma/Marginal Zone Lymphoma by Therapeutic Intervention

Percentage of Patients Percentage of Patients

Rituximab Chemotherapy and Chemotherapy Splenectomy “Watch and Wait”

Variable (n ⴝ 26)* Rituximab (n ⴝ 6) (n ⴝ 11) P† (n ⴝ 10) (n ⴝ 17) P‡

Age ⬎60 y 65 50 64 .82 40 53 .67

Zubrod performance status ⬎1 8 0 0 .99 0 0 .82
Rai stage ⬎2 50 67 27 .26 80 29 .06
CLL score ⬎2§ 4 33 9 .09 0 0 .06
No prior therapy 81 83 91 .85 90 100 .32
␤2-microglobulin ⬎4 mg/L 54 50 27 .35 50 19 .12
LDH ⬎1 ⫻ ULN (618 IU/L) 42 50 64 .47 40 35 .67
Hemoglobin ⬍11 g/dL 38 17 36 .74 40 24 .75
Absolute lymphocyte count ⬎5 ⫻ 109/L 85 67 88 .44 0 0 .0001

CLL: chronic lymphocytic leukemia; LDH: lactate dehydrogenase; ULN: upper limit of normal.
* Includes 25 patients treated with rituximab and 1 patient treated with alemutzumab.
† The P values were calculated by comparing pretreatment characteristics between the 3 treatment groups (i.e., rituximab, chemotherapy and rituximab, and chemotherapy) (Fisher test).
‡ The P values were calculated by comparing baseline characteristics between the 5 groups (i.e., rituximab, chemotherapy and rituximab, chemotherapy, splenectomy, and the “watch and wait” approach) (Fisher
test).
§ See Matutes et al.25

had documented cryoglobulinemia with a positive di- aly (7 patients), progressive organomegaly and lymph-
rect Coombs test result. adenopathy (6 patients), symptomatic worsening ane-
mia (5 patients), B-symptoms (3 patients), blood
Therapy lymphocyte count doubling in ⬍1 year (3 patients),
Forty-three patients required systemic therapy. Pa- thrombocytopenia (1 patient), and lymphoma-associ-
tient characteristics according to therapeutic interven- ated collagen vascular disease (1 patient); 2) for che-
tion are shown in Table 3. Twenty-six patients re- motherapy plus rituximab (6 patients), symptomatic
ceived immunotherapy (rituximab, 25 patients; splenomegaly and lymphadenopathy (4 patients), B-
alemtuzumab, 1 patient); 6 patients received chemo- symptoms (1 patient), and worsening anemia and
therapy plus rituximab (FCR, 5 patients; R-FMD, 1 thrombocytopenia (1 patient); and 3) for chemother-
patient), and 11 patients received chemotherapy (flu- apy (11 patients), symptomatic splenomegaly (5 pa-
darabine, 2 patients; fludarabine plus prednisone, 1 tients), symptomatic cytopenias (2 patients), blood
patient; fludarabine plus cyclophosphamide, 3 pa- lymphocyte count doubling in ⬍1 year (2 patients),
tients; cladribine, 3 patients; fludarabine, cyclophos- autoimmune hemolytic anemia (1 patient), and B-
phamide, and granulocyte-macrophage– colony-stim- symptoms (1 patients). Assignment to different thera-
ulating factor [GM-CSF], 1 patient; and fractionated pies was based on therapy availability (e.g., patients
cyclophosphamide, vincristine, liposomal daunorubi- who required systemic therapy prior to the rituximab
cin, dexamethasone, and GM-CSF, 1 patient). Pre- era were treated with chemotherapy alone), patient
treatment characteristics were similar between the 3 preference, and physician discretion.
groups (Table 3). Ten patients underwent splenec-
tomy alone, and 7 additional patients who underwent Response to Therapy
splenectomy required subsequent systemic therapy. Overall, 26% of patients who received systemic ther-
In 17 patients, a “watch-and-wait” approach was used. apy achieved CR, 9% of patients had a CRu, and 44% of
Patients in the splenectomy and observation groups patients achieved PR. Response by therapy is summa-
had normal absolute lymphocyte counts, as expected, rized in Table 4.
compared with high rates of patients with elevated
absolute lymphocyte counts in the rituximab, che- Survival
motherapy plus rituximab, and chemotherapy The event charts in Figure 1 show the patients’ status.
groups (P ⫽ .0001) (Table 3). The median follow-up of surviving patients was 2.7
Treatment was deemed necessary at the time of years (range, 0.1-16.9 years). Fifteen patients have
disease progression, which was defined as follows: 1) died. Causes of death were as follows: progressive
for rituximab (26 patients), symptomatic splenomeg- disease in 5 patients (chemotherapy, 4 patients; ale-

TABLE 4
Response in 43 Patients who Required Systemic Therapy*
Response Rituximab (n ⴝ 26)†
CR 8 (31)
Cru 3 (12)
PR 12 (46)
CR, CRu, and
PR 23 (88)
CR: complete remission; CRu: unconfirmed CR; PR: partial remission.
* Among the 10 patients who underwent splenectomy only, 3 patients had a CR and 3 patients had a PR.
† Twenty-five of 26 patients received rituximab.
‡ Chemotherapy plus rituximab.
mtuzumab, 1 patient), secondary cancer in 3 patients
(watch-and-wait, 2 patients; splenectomy, 1 patient);
progressive multifocal encephalopathy, 1 patient (che-
motherapy), severe congestive heart failure, 1 patient
(rituximab), liver failure, 1 patient (splenectomy), and
unknown in 4 patients (chemotherapy, 3 patients; rit-
uximab, 1 patient). The median survival duration of
the 70 patients was 8.5 years (95% confidence interval,
6.3-22.1⫹ years). Eighty-six percent of patients re-
mained alive at 3 years (Fig. 2A).
Survival rates were higher in the chemotherapy
plus rituximab group than in the rituximab group and
higher in the rituximab group than in the chemother-
apy group (P ⫽ .047) (Fig. 2B). The median follow-up
of surviving patients in the rituximab group was 2.5
years (range, 0.1-5.2 years), and 3 of 26 patients (12%)
have died. No deaths were noted among the 6 patients
in the chemotherapy plus rituximab group after a me-
dian follow-up of 3.4 years (range, 0.2-5.2 years). Eight
of 11 patients (73%) in the chemotherapy group died
after a median follow-up of 6.8 years (range, 6.3-16.9
years). Two of 10 patients (20%) in the splenectomy
group have died after a median follow-up of 2.4 years
(range, 0.8-7.6 years); at 3 years, 89% of those patients
remained alive. The median follow-up of patients in
the “watch-and-wait” group was 2.7 years (range, 0.2-
7.1 years). Two of 17 patients (12%) in that group have
died, and their 3-year survival rate was 83%.
On univariate analysis, the only factors that cor-
related with longer survival in the 70 patients were age
younger than 60 years (P ⫽ .01) and rituximab with or
without chemotherapy (P ⫽ .047). There was no cor-
relation between survival and lactate dehydrogenase
or ␤2-microglobulin levels, absolute lymphocyte
counts, or percentage of CD20 in the bone marrow or
peripheral blood.
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Rituximab for Splenic Marginal Zone Lymphoma/Tsimberidou et al. 129
No. of Patients (%)
Chemoimmunotherapy (n ⴝ 6)‡ Chemotherapy (n ⴝ 11) Total (n ⴝ 43)
1 (17) 2 (18) 11 (26)
1 (17) 0 4 (9)
3 (50) 4 (36) 19 (44)
5 (83) 6 (55) 34 (79)
Failure Free Survival
The median FFS duration of 70 patients was 5.7 years.
Seventy-five percent of 70 patients remained failure
free at 3 years (Fig. 3A). Treatment failure occurred in
a total of 26 patients, including 6 of 26 patients (23%)
in the rituximab group, 1 of 6 patients (17%) in the
chemotherapy plus rituximab group, and 11 of 11
patients (100%) in the chemotherapy group (P ⫽ .06)
(Fig. 3B).
Five of 10 patients (50%) in the splenectomy
group experienced treatment failure, and their 3-year
FFS rate was 80%. Three of 17 patients (18%) in the
observation group developed progressive disease or
died. No factor was identified that predicted longer
FFS. There was no significant difference in FFS be-
tween the 26 patients who received rituximab and the
10 patients who underwent splenectomy as their first
treatment at M. D. Anderson (P ⫽ .56).
Response, Survival, and FFS with Rituximab With or
Without Chemotherapy
Nineteen patients received ⬎1 therapy. Therefore, some
patients received sequential chemotherapy plus ritux-
imab and rituximab alone. To examine the role of these
therapies in clinical outcome, patients who received
chemotherapy plus rituximab combination therapy at
any time, irrespective of other therapies, were consid-
ered. In total, 12 patients had received chemotherapy
plus rituximab at 1 time. The median follow-up of sur-
viving patients in this group was 2.9 years (range, 0.2-5.2
years), and their overall response rate was 83% (CR, 4
patients; CRu, 2 patients; and PR, 4 patients). The me-
dian survival duration has not been reached; however,
100% of patients remained alive at 3 years (Fig. 4A). One
patient (8%) died at 3.5 years. The median FFS duration
is 3.9 years, and 64% of patients had not experienced
treatment failure at 3 years (Fig. 4A).
 10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
130 CANCER July 1, 2006 / Volume 107 / Number 1

FIGURE 1. (A) Disease course and survival status of 51 patients who received 1 treatment modality at The University of Texas M. D. Anderson Cancer Center
(MDACC): rituximab alone (Rit), immunotherapy (ImmunoRx), chemotherapy (Chemother) and rituximab (Rit ⫹ Chemoth), chemotherapy (chemoth), splenectomy, or
a “watch-and-wait” approach. (B) Disease course and status are illustrated for 19 patients who required ⬎1 treatment (Rx) modality.

Rituximab for Splenic Marginal Zone Lymphoma/Tsimberidou et al.
FIGURE 2. (A) Overall survival in 70 patients with splenic marginal zone
lymphoma/marginal zone lymphoma (SMZL). (B) Failure-free survival in 70
patients with SMZL.
In total, 31 patients had received rituximab at 1
time. The overall response rate was 93.5% (CR, 10
patients; CRu, 3 patients; and PR, 16 patients). The
median follow-up of surviving patients was 3.1 years
(range, 0.1-6.1 years). At the time of last follow-up, 3
patients had died. One patient died of preexisting
congestive heart failure at age 84 years, with stable
disease 11 months after rituximab therapy; another
patient died of progressive disease at age 76 years, 5.6
years after rituximab therapy and subsequent salvage
therapies; and the third patient was lost to follow-up
and died at age 73 years, 5 years after rituximab ther-
apy. The median survival duration had not been
reached at the time of last follow-up, and 97% of
patients remained alive at 3 years (Fig. 4B). The me-
dian FFS duration was 2.9 years, and 88% of patients
had not experienced treatment failure at 3 years
(Fig. 4B).
10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
131
FIGURE 3. (A) Overall survival in 43 patients by therapy. (B) Failure-free
survival in 43 patients by therapy. Chemo: chemotherapy; Immuno:
immunotherapy.
Comparison of Rituximab with Splenectomy
Changes in bone marrow and blood counts among
patients who received rituximab (25 patients) were
compared with changes among patients who under-
went splenectomy as initial therapy (17 patients, in-
cluding 7 patients who received subsequent therapies)
(Table 5). Rituximab resulted in the disappearance of
a palpable spleen in 23 patients (92%). Rituximab also
was superior to splenectomy in normalizing white
blood cell counts (P⬍.001) and absolute lymphocyte
counts (P⬍.001). Splenectomy resulted in higher
platelet counts compared with rituximab (P⬍.001).
Differences in hemoglobin levels and bone marrow
cellularity did not reach statistical significance, but a
trend toward a significantly lower proportion of lym-
phocytes was noted in patients who received ritux-
imab (P ⫽ .10).
In patients who underwent splenectomy, the pat-
tern of bone marrow infiltration by lymphocytes/lym-

132 CANCER July 1, 2006 / Volume 107 / Number 1
FIGURE 4. (A) Survival and failure-free survival in patients who received
chemotherapy plus rituximab at any time. (B) Survival and failure-free survival
in patients who received rituximab at any time.
phoma cells changed in 3 of 9 patients who underwent
a bone marrow biopsy after splenectomy. One patient
had a nodular interstitial pattern that changed into a
nodular pattern; 1 patient had an interstitial diffuse
pattern that changed into an interstitial nodular pat-
tern, and 1 patient had a nodular pattern that changed
into a nodular interstitial pattern.
Among the patients who received rituximab who
had “paired” assessments for patterns of bone marrow
infiltration by lymphocytes/lymphoma cells, 10 pa-
tients had no evidence of disease in the bone marrow
after therapy. Eight of those 10 patients had available
biopsies prior to rituximab therapy that demonstrated
an interstitial (4 patients), nodular (2 patients), or
interstitial diffuse (1 patient) pattern or lymphoid ag-
gregates (1 patient).
Other Malignancies
Seventeen of 70 patients (24%) had another malig-
nancy. Eight of those 17 patients (47%) had a malig-
10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
nancy before their diagnosis of splenic lymphoma.
The distribution of cancers was as follows: basal cell or
squamous cell skin carcinoma in 4 patients, breast
cancer and a squamous cell carcinoma in 1 patient,
vulvar squamous cell carcinoma in 1 patient, bladder
cancer in 1 patient, and melanoma in 1 patient. Eight
of 17 patients (47%) developed a secondary malig-
nancy after their diagnosis of splenic lymphoma, in-
cluding breast cancer in 3 patients, mesencephalic/
thalamic large cell lymphoma in 1 patient, Hodgkin
lymphoma in 1 patient, testicular cancer in 1 patient,
prostate cancer in 1 patient, and basal cell carcinoma
in 1 patient. One patient had rectal cancer prior to and
also developed a secondary meningioma after the di-
agnosis of splenic lymphoma. There were 9 patients
who developed a cancer after their diagnosis or treat-
ment of SMZL, including 2 patients in the observation
group, 3 patients in the chemotherapy group, 2 pa-
tients in the rituximab group, and 2 patients in the
chemotherapy plus rituximab group.
DISCUSSION
The CR, FFS, and survival rates were found to be
higher with rituximab alone and in combination with
a purine analog-based therapy (FCR or R-FMD) than
with chemotherapy alone. Our results appear to be in
line with published data that have demonstrated sim-
ilar survival rates in patients with SMZL.8 –11,13,28,29
However, the proportion of patients who received
therapy was higher in the current study compared
with others, suggesting that higher risk patients may
have been referred to our department.
The high response rate with rituximab alone was
encouraging, including its efficacy in patients who had
adverse prognostic features, such as older age and
high lactate dehydrogenase or ␤2-microglobulin lev-
els. The current study data demonstrated that ritux-
imab effectively controls SMZL, as evidenced by im-
provement in white blood cells, absolute lymphocyte
counts, and splenomegaly, and suggested that ritux-
imab therapy may be proposed as the treatment of
choice, at least in older patients with SMZL who have
comorbid diseases. The high response rate with ritux-
imab may be associated with higher levels of surface
CD20 molecules per cell on the circulating lympho-
cytes in patients with SMZL compared with the levels
in patients with CLL.26
Three of 6 patients who received chemotherapy
plus rituximab in the current study had a PR because
of prolonged cytopenia, which is typical of myelosup-
pressive therapy. Although it is difficult to interpret
these data because of the very small numbers of pa-
tients, prolonged FFS and survival were observed in
 10970142, 2006, 1, Downloaded from https://acsjournals.onlinelibrary.wiley.com/doi/10.1002/cncr.21931, Wiley Online Library on [09/03/2024]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License
Rituximab for Splenic Marginal Zone Lymphoma/Tsimberidou et al. 133

TABLE 5
Changes in Complete Blood Counts and Bone Marrow According to Treatment with Splenectomy or Rituximab

Splenectomy (n ⴝ 17)* Rituximab (n ⴝ 25)

Wilcoxan Wilcoxan
Median (Range) Median (Range)
Test For Test For
No. of Paired No. of Paired Wilcoxon
Variable Before After Patients* Data (P)† Change Before After Patients* Data (P)† Change Test P‡

Hgb (g/dL) 10.1 (7.5-13.4) 12.3 (8.6-15.1) 15 .12 1.1 (- 2.2, 4.3) 11.5 (7.1-14.7) 12.7 (7.8-16) 23 .001 1 (- 1.1, 4.6) .53
WBC (⫻ 109/L) 15.2 (2.5-64.1) 16.5 (9.1-68.8) 15 .003 9.2 (- 3.2, 44.9) 21.2 (1.8-181) 4.4 (1.9-12.8) 23 ⬍.001 -15.4 (- 176, 1.7) ⬍.001
Platelets
(⫻ 109/L) 112 (1-216) 321 (123-713) 15 ⬍.001 178 (- 58, 682) 143 (52-288) 180 (28-293) 23 .007 31 (- 65, 109) ⬍.001
ALC (⫻ 109/L) 6.5 (0.4-48.9) 4.7 (0.9-58.5) 14 .24 0.6 (- 12.7,13) 17.2 (0.4-164) 1.19 (0.5-2.9) 23 ⬍.001 -14.4 (- 163, 0.4) ⬍.001
Spleen size
(cm) 9 (0-24) 0 (0-0) 17 ⬍.001 -9 (- 24, 0) 6 (0-20) 0 (0-3) 23 ⬍.001 -7 (- 20, 1) .217
BM cell (%) 55 (20-90) 25 (5-80) 9 .04 -25 (- 65, 10) 45 (5-90) 30 (10-100) 17 .03 -10 (- 60, 20) .316
BM lymph (%) 56 (4-84) 25.8 (12-78) 9 .26 -10 (- 52.2, 18) 48 (3-84) 19 (7-74) 18 ⬍.001 -76 (- 62, 10) .117

Hgb: hemoglobin; WBC: white blood cells; ALC: absolute lymphocyte count; BM cell: bone marrow cellularity; BM lymph: bone marrow lymphocytes.
* Values shown are the number of patients with available paired data.
† The Wilcoxon signed rank test was used for comparison of the paired available data (before vs. after therapy) for continuous variables.
‡ The Wilcoxon rank sum test was used to examine the difference of changes between the 2 groups of patients for continuous variables.

the patients who received chemotherapy plus ritux- It is noteworthy that flow analysis identified rela-
imab. tively high rates of CD5 positivity in the current series,
The results of the current study suggest that rit- even though SMZL has been considered a CD5-nega-
uximab-based therapy may be more effective than tive lymphoma. This discrepancy may be explained by
chemotherapy alone. However, this cannot be a de- differences in the sensitivity of flow-cytometry and
finitive conclusion given the retrospective nature of immunocytochemistry methods or by the acquisition
the analysis and the relatively small number of pa- of different cell phenotypes according to their micro-
tients evaluated. environment,5 which is compatible with the high pro-
Earlier experiences with chemotherapy in patients portion of patients with leukemic-phase disease noted
with SMZL showed some benefit with alkylating in the current study.
agents, although lower survival rates were noted in 1 In the current series, the incidence of other ma-
study among patients who initially were treated with lignancies appeared to be higher than that in other
chemotherapy compared with other treatments.9 Pre- lymphoproliferative disorders. However, approxi-
vious studies have shown that fludarabine induces mately 50% of these cancers were diagnosed prior to
responses even in the salvage setting, but the majority diagnosis of or therapy for SMZL, which suggests a
of patients eventually develop disease recurrence.14 –16 pathogenetic role for inactivation of tumor suppressor
Treatment with 2-chlorodeoxyadenosine was associ- genes, such as p53. Indeed, loss or mutations of p53
ated with poor outcomes and high toxicity in splenec- have been associated with a poor outcome in patients
tomized patients with SLVL in 1 study,17 but it was with SMZL.34,35
associated with favorable outcomes in another study SMZLs are heterogeneous diseases and, thus, may
that used a different dose and schedule.18 respond variably to therapy. Both mutated and unmu-
Several factors have been described that predict tated cases of SMZL have been reported.36 The heter-
clinical outcome in patients with SMZL.6,8,9,28,30 –32 Cy- ogeneity of SMZL is considered to reflect the hetero-
togenetics, e.g., t(11;18), also reportedly is an adverse geneity of their nonneoplastic counterparts.37 Some
prognostic factor of tumor response to oral alkylating SMZLs are antigen driven, and differences in antigen
agents in patients with low-grade gastric lymphoma of influx (through blood or lymph) and antigenic nature
mucosa-associated lymphoid tissue.33 However, the (T-cell dependent or not) may enhance their hetero-
only factors in the current study that predicted shorter geneity, which largely depends on the anatomic site
survival among patients who required therapy were from which the lymphoma arises.37
age ⬎60 years and treatment with chemotherapy. The The results of the current study combined with
difference may be associated with the activity of rit- data demonstrating the distinct biology of SMZL sug-
uximab-based therapies in this group of patients. gest that carefully designed clinical trials with the ob-

134 CANCER July 1, 2006 / Volume 107 / Number 1
jective of curing SMZL should be developed separately
from trials for other lymphomas. To our knowledge,
prospective studies of SMZL are nonexistent, and cur-
rent therapies are based on case reports, retrospective
analyses of relatively small numbers of patients, or the
application of treatments that are effective in other
lymphomas. Rituximab-based regimens appear to be
superior to chemotherapy; therefore, these therapies
should be explored further in patients with SMZL.
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