VOLUME 23 d

NUMBER 26 d
SEPTEMBER 10 2005

JOURNAL OF CLINICAL ONCOLOGY R E V I E W A R T I C L E

Current Treatment Approaches for

Mantle-Cell Lymphoma
Thomas E. Witzig
From the Mayo Clinic College of
Medicine and Mayo Foundation A B S T R A C T
Rochester, MN.

Submitted March 15, 2005; accepted

July 7, 2005.
Supported in part by Grants No.
CA97274 and CA25224 from the
National Institutes of Health and the
National Cancer Institute.
Author’s disclosures of potential
conflicts of interest are found at the
end of this article.
Address reprint requests to Thomas E.
Witzig, MD, Mayo Clinic, Stabile 628,
200 First St SW, Rochester, MN 55905;
e-mail: Witzig@mayo.edu.
 2005 by American Society of Clinical
Oncology
0732-183X/05/2326-6409/$20.00
DOI: 10.1200/JCO.2005.55.017
Mantle-cell lymphoma (MCL) is now recognized as a distinct clinicopathologic subtype of
B-cell non-Hodgkin’s lymphoma. Patients with MCL are typically older adults with a male pre-
dominance and usually present with stage IV disease. The cells are characterized as CD20⫹
CD5⫹ CD23⫺ with a t(11;14)(q13;q32) and cyclin D1 overexpression on immunohistochem-
istry. Response to chemotherapy usually results in a tumor response but unmaintained remis-
sions are short and the median survival is 3 to 4 years. The treatment approach to newly
diagnosed patients with MCL depends on the patient’s eligibility for stem cell transplantation
(SCT). Those who are eligible are usually treated with either rituximab-CHOP (cyclophospha-
mide, doxorubicin, vincristine, and prednisone) followed by SCT or rituximab-HyperCVAD (cy-
clophosphamide, vincristine, doxorubicin, decadron, cytarabine, and methotrexate) followed
by observation. The purine nucleoside analogues also have activity as single agents and with
rituximab. Unfortunately none of these approaches can definitively cure patients with MCL,
and new agents are needed. Recent studies in patients with relapsed MCL have shown sub-
stantial antitumor activity of single-agent bortezomib, single-agent temsirolimus, and the
combination of thalidomide and rituximab. Studies integrating these novel agents earlier in
the disease course or in combination with each other will hopefully produce more durable
responses with less toxicity.
J Clin Oncol 23:6409-6414.  2005 by American Society of Clinical Oncology

INTRODUCTION scribed10-12 and are discussed in this issue

Mantle-cell lymphoma (MCL) is a distinct
clinical type of B-cell non-Hodgkin’s lym-
phoma that accounts for approximately
8% of all lymphoma diagnoses. This dis-
order tends to occur in older adults with
a higher incidence in males.1 The immuno-
phenotype of the malignant cells in MCL is
typically CD20⫹, CD5⫹, CD10⫺, CD23⫺,
light chain restricted, and BCL-1⫹ (B-cell
lymphoma 1, also known as cyclin-D1 or
CCND1).2,3 Cyclin-D1 overexpression
occurs as a result of a translocation of the
cyclin-D1 gene on 11q13 to the promoter
of the immunoglobulin heavy chain locus
on 14q32.4 This translocation can be
detected in the tumor cells by classical cyto-
genetics or fluorescence in situ hybridiza-
tion (FISH; Fig 1).5-9 Additional genetic
and proteomic abnormalities have been de-
by Pasqual et al.
The initial diagnostic evaluation in-
cludes computed tomography scans of
the chest, abdomen, and pelvis; a CBC;
blood chemistries for renal and liver func-
tion; and an aspiration and biopsy of the
bone marrow. Many patients have circulat-
ing lymphoma cells that are detectable by
a peripheral blood smear or by flow cytom-
etry.13,14 An excisional lymph node biopsy
should be evaluated by an expert hemato-
pathologist with immunophenotyping
and cyclin-D1 staining. In routine clinical
practice, cytogenetic analysis (classical or
FISH) is necessary only in cases in which
the cyclin D1 stain is equivocal or the his-
tology or immunophenotype are difficult
to interpret, as can occur when the diag-
nostic tissue is from the blood or a bone

6409

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Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
 Thomas E. Witzig
A B
Fig 1. Results of fluorescence in situ hybridization (FISH). (A) Healthy cell
showing two signals each for CCND1 on chromosome 11 (orange) and the
IgH gene on chromosome 14 (green). (B) Tumor cells from a patient with
mantle-cell lymphoma demonstrating the yellow signal that results from the
11;14 translocation that is characteristic of MCL. (Photograph courtesy of
G. Dewald, PhD).
marrow aspirate. Staging tests usually demonstrate ad-
vanced stage (III or IV), and involvement of extranodal
sites such as the intestinal tract, kidney, bone marrow,
and peripheral blood is common. Routine upper and
lower endoscopy is not necessary unless the patient has
symptoms such as gastrointestinal hemorrhage or pain
suggestive of involvement.15
The clinical course of MCL is characterized by a very
high overall response rate (ORR) to induction treatment
with a relatively short time to progression and a poor overall
survival (OS) of approximately 3 to 4 years.1,16-19 There
is currently no standard therapy for newly diagnosed or
relapsed MCL. Patients with massive splenomegaly often
benefit from splenectomy to relieve symptoms and improve
blood counts.20,21 Many regimens have been demonstrated
to be highly active in producing tumor responses, but re-
lapse typically occurs and patients usually die of their dis-
ease. New agents and approaches to MCL are needed and
indeed are becoming reality as discussed below. This brief
review will discuss each major treatment modality and sug-
gest a treatment strategy based on current data.
RITUXIMAB
The anti-CD20 antibody rituximab (R-) has been tested as
a single agent for both previously untreated and relapsed
MCL. In the study by Ghielmini et al,22 88 patients received
four standard doses of rituximab and the response rate at
week 12 was 27% with 2% complete responses. Among
the 34 patients who were previously untreated, the response
rate was 27% with 3% complete response rate.22 Others have
demonstrated a somewhat higher response rate for MCL
patients of about 33-38%.23,24 Rituximab is generally not
adequate as a single-agent for MCL but it is in common
use in combination with standard chemotherapy regimens.
CHEMOTHERAPY
Although there are many potential induction regimens
for MCL, they can be separated into three general catego-
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Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
ries: (1) standard doxorubicin-containing regimens
such as R-CHOP (cyclophosphamide, doxorubicin, vin-
cristine, and prednisone); (2) intensive combination chem-
otherapy regimens, including anti-metabolites such as
R-HyperCVAD (cyclophosphamide, vincristine, doxoru-
bicin, decadron, cytarabine, and methotrexate); and (3)
purine analog–based regimens such as R-FCM (fludara-
bine, cyclophosphamide, mitoxantrone). Each of these
regimens typically produces response rates in the 80%
to 95% range. A single-arm phase II study by Howard
et al25 treated 40 new MCL patients with R-CHOP and re-
ported a 96% overall and 48% complete response rates.
The benefit of R-CHOP was confirmed in a randomized
trial in which 122 patients with stage III/IV MCL were ran-
domly assigned to CHOP (n Z 60) or R-CHOP (n Z
62).26 The response rate was 94% versus 75% and the com-
plete response rate 34% versus 7% for R-CHOP and CHOP,
respectively. Patients treated with R-CHOP had a longer
time to progression, but there was no survival advantage
and the majority of patients relapsed within 2 years, such
that R-CHOP cannot be considered curative therapy.
Romaguera et al27 reported the results of 100 untreated
MCL patients treated with R-hyperCVAD. Patients received
three cycles of rituximab, cyclophosphamide, vincristine,
doxorubicin, and dexamethasone (R-HCVAD) alternating
with 3 cycles of rituximab/methotrexate/cytarabine with-
out transplantation or maintenance. Ninety-seven patients
were assessable and 87% went into complete remission. The
median follow-up was 40 months and the 3-year failure
free survival and OS were 67% and 81%, respectively. Age,
beta-2 microglobulin, and gastrointestinal involvement
were adverse prognostic factors. For example, if the patient
was ⬍ 65 years of age, 78% were free of disease at 3 years
compared with 46% if the patient’s age was ⬎ 65. There
were 5% toxic deaths, and four additional patients have
developed myelodysplastic syndrome (MDS) or acute leu-
kemia after treatment.
The purine nucleoside analogs also have single-agent
activity in MCL. Studies with fludarabine have shown
a 33% to 41% response rate as a single agent28,29 and
63% when combined with cyclophosphamide.30 A recent
randomized study demonstrated that rituximab combined
with fludarabine, cyclophosphamide, and mitoxantrone
(R-FCM) was superior to FCM alone for patients with re-
lapsed MCL.31 2-Chlorodeoxyadenosine (2-CDA) has also
shown an 81% response rate as a single agent32 and 100%
response rate with a median duration of response of 24
months when combined with mitoxantrone.33 A study
of 2-CDA and rituximab for patients with untreated MCL
who are not candidates for stem cell transplantation is
ongoing in the North Central Cancer Treatment Group.
Patients with relapsed MCL had a 54% response rate
and 21% complete response rate to 2-CDA with a median
time to progression of 5.4 months.34
JOURNAL OF CLINICAL ONCOLOGY
 Mantle-Cell Lymphoma
RADIOIMMUNOTHERAPY
There have been limited studies using single-agent radio-
immunotherapy (RIT) for patients with relapsed MCL. In
a phase I trial of 90Yttrium-ibritumomab tiuxetan, there
were 3 patients with relapsed MCL and none responded.35
A trial devoted specifically to patients with relapsed
MCL demonstrated a 33% (five of 15) response rate to
90
Yttrium-ibritumomab tiuxetan.36 The reported response
to RIT (90Y-ibritumomab or 131I-tositumomab) as single
agents is similar to rituximab. Current approaches are
now combining RIT with chemotherapy at the time of in-
duction. For example, the Eastern Cooperative Oncology
Group recently completed a phase II trial that delivered
R-CHOP ⫻ 4 cycles followed by a standard dose of
90
Yttrium-ibritumomab tiuxetan in the first remission.
Another strategy is using 131Iodine-tositumomab as initial
treatment followed by R-CHOP.36a These approaches of
combining RIT and chemotherapy seem to be safe;
whether they will produce a longer time to progression
or survival than observed with R-CHOP alone is yet to
be determined.
TRANSPLANTATION
High-dose therapy with stem cell transplantation (SCT)
has been studied extensively in MCL.37-45 These studies
fall into several categories: standard autologous or allo-
geneic SCT, autologous SCT with rituximab used as
part of the SCT conditioning, autologous SCT with RIT
as part of the preparative regimen, and reduced-intensity
allogeneic SCT. There has been only one trial that ran-
domly assigned patients who had responded with a com-
plete or partial remission after induction chemotherapy
to autologous SCT or interferon maintenance.43 Two hun-
dred sixty-nine patients were enrolled, but only 122 were
assessable. In patients receiving SCT, the median progres-
sion-free survival rate was 39 months compared with 17
months in the interferon arm, with 3-year progression-
free survival rates of 54% and 25% for the SCT and inter-
feron arms, respectively (P Z .01). In subset analysis,
patients who underwent transplantation in complete re-
mission received greater relative benefit from the trans-
plant maneuver. At a median follow-up of 34 months,
the 2-year survival probability with SCT was 86% com-
pared with 82% with interferon (P Z NS). The survival
curves did not show a plateau for either treatment arm.
Other trials using SCT generally have been small and
retrospective, but they do provide data useful in making
decisions about patient management. Lefrere et al39 re-
cently reported a median survival of more than 6 years
with a median progression-free survival of 51 months in
patients receiving autologous SCT for MCL in first com-
plete remission. Approaches to improve the preparative
regimen for autologous SCT include adding rituximab
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Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
or a radioimmunoconjugate. Mangel et al41 treated 20 pa-
tients with new MCL with CHOP followed by stem cell
mobilization with rituximab. Patients then underwent
standard autologous SCT with chemotherapy condition-
ing followed by rituximab maintenance (rituximab ⫻ 4
doses at 8 and 24 weeks post-SCT). The progression-
free survival at 3 years was 89% for SCT compared with
29% for matched historical controls; OS at 3 years was
88% and 65%, respectively. Gianni et al46 also used ritux-
imab as part of the preparative regimen for autologous
stem cell collection, but did not use rituximab mainte-
nance. They treated 28 patients, and 24 remain in com-
plete remission with a median follow-up of 35 months.
These results were superior to a matched control group.
Another approach is to use RIT as part of the prepar-
ative regimen. This approach was pioneered for MCL by
Gopal et al44 using high-dose 131I-tositumomab, etopo-
side, cyclophosphamide with stem cell support in 16 pa-
tients with relapsed MCL. The response rate was 100%
with 91% complete responses; 93% survival at 3 years
and 61% of patients remain progression free at 3 years.
There have been no treatment-related deaths. Other stud-
ies using 90Yttrium-ibritumomab tiuxetan with chemo-
therapy and SCT are in progress.47,48
Several reports have included a mix of patients treated
with either autologous or allogeneic transplantation.
Kasamon et al38 recently reported on 58 MCL patients
who had undergone SCT (19 allogeneic and 39 autolo-
gous). The estimated median progression-free survival
was 43 months for the entire cohort and the actuarial
3-year progression-free survival was 51%. Sixty-four
patients underwent transplantation in first complete re-
mission and these patients had a statistically significant,
longer progression-free survival than if the transplant
were performed at relapse. There was no difference in
the progression-free survival between patients who re-
ceived an allogeneic versus an autologous SCT. Patients
failing to benefit from an autologous SCT underwent
successful salvage treatment with allogeneic SCT using
reduced-intensity conditioning with fludarabine and
total-body irradiation.42
NEW AGENTS FOR MCL
Recent studies have identified new treatment approaches
for relapsed MCL. Three groups of agents have shown ac-
tivity: proteosome inhibitors, mammalian target of rapa-
mycin (mTOR) inhibitors, and thalidomide. Bortezomib
is an inhibitor of the intracellular protein degradation
pathway known as the proteosome and is United States
Food and Drug Administration approved for relapsed
multiple myeloma. Studies of bortezomib for relapsed
MCL have shown antitumor activity. Goy et al49 treated
33 patients with bortezomib 1.5 mg/m2 on days 1, 4, 8,
and 11 every 21 days for a maximum of six cycles.
6411
 Thomas E. Witzig
Twenty-nine patients were assessable for response and 12
(41%) responded, six with complete response. The median
time to progression was not reached with a median
follow-up of 9.3 months. O’Connor et al50 used the same
schedule of bortezomib in 11 patients with relapsed MCL.
Patients were required to have received no more then three
prior chemotherapy regimens and to be 3 or more months
beyond prior rituximab treatment. Five (50%) of 10 assess-
able patients responded (one complete remission) with a
duration of response ranging from 6 to 19 months.
Thalidomide, another agent used predominantly for
the treatment of multiple myeloma, has been evaluated
in MCL alone and in combination. Kaufmann et al51 re-
cently reported on a study of 16 patients who were treated
with rituximab 375 mg/m2 once weekly for four weeks
together with thalidomide 200 mg/day orally with a dose
escalation to 400 mg/day on day 15. The rationale for this
combination was to target the tumor cells with rituximab
and the microenvironment with thalidomide. The median
time from MCL diagnosis to protocol treatment was 21
months. All patients had previously received CHOP chem-
otherapy and three had had a prior transplant. However,
only three had received rituximab previously, and 50% (8
of 16) had received only one prior therapy. The rituximab/
thalidomide combination produced a high ORR of 81%
(13/16) with five complete and eight partial responses.
The median time to progression was 20 months, and eight
of the 13 responders subsequently relapsed. There were
two thromboembolic events.
The mTOR kinase regulates mRNA translation by
phosphorylation of two critical substrates—eukaryotic ini-
tiation factor 4E binding protein and p70S6 kinase. These
phosphorylation events enhance translation of cyclin-D1
mRNA into cyclin-D1 protein. Activity of mTOR can be
inhibited by rapamycin analogs such as temsirolimus
(also known as CCI-779). A recent trial of temsirolimus
utilized 250 mg as a flat dose intravenously weekly for
a maximum of 12 months.52 Thirty-five patients were ac-
crued of whom 38% responded (one complete and 12 par-
tial remissions). The median time to progression was 6.8
months. The dose-limiting adverse effect in this study pop-
ulation was reversible thrombocytopenia. Ongoing trials
are testing lower doses of temsirolimus (25 mg weekly)
to learn if these will be better tolerated while maintaining
response. It is clear that inhibiting this signal transduction
pathway can produce substantial tumor responses in pa-
tients with heavily pretreated MCL.
CURRENT TREATMENT APPROACHES
On the basis of the generally less-than-satisfactory outcomes
with current cytotoxic approaches, consideration should be
given to a quality clinical trial as the initial treatment for
MCL as well as at relapse. For those who do not wish to par-
ticipate or for whom a suitable trial is not available, the pre-
6412
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Copyright © 2005 by the American Society of Clinical Oncology. All rights reserved.
ceding discussion of therapeutic agents provides a
framework to recommend a treatment strategy for patients
with MCL as of 2005 (Fig 2). Before choosing which regimen
to use, the treating physician must take into account the
patient’s age, performance status, and other comorbidities
and decide whether the patient will ever be a candidate for
high-dose therapy with stem cell rescue.
If the patient is ⬍ 75 years old and in excellent phys-
ical condition, then autologous SCT can be considered
a potential option. This influences the initial treatment
approach because if stem cell harvest is anticipated,
then the use of a purine nucleoside analog as induction
should be avoided or limited in the number of cycles.
The most commonly used regimens are R-CHOP induc-
tion followed by stem cell harvest and SCT in first remis-
sion or R-hyperCVAD without transplantation if the
patient achieves a complete response. As noted earlier,
the results with R-CHOP and autologous SCT in first
complete remission are similar to that reported with
R-HyperCVAD without SCT. Both approaches can be
considered ‘‘aggressive’’ because they are associated with
similar treatment-related mortality and risk of MDS. If
R-CHOP ⫹ SCT is chosen, one should consider using
an investigational preparative regimen for the SCT that
includes in vivo purging with rituximab or a radioimmu-
notherapy agent because these approaches may add effi-
cacy without added toxicity.
If the patient is elderly and not a SCT candidate, the
use of a rituximab-containing chemotherapy regimen is
appropriate. Purine nucleoside analogs with rituximab
may be especially useful in the elderly patient population
or those who cannot tolerate anthracyclines.
Those patients who relapse after these induction regi-
mens should be considered for novel treatment programs
or, if the patient had a long time to progression from the
New untreated mantle cell lymphoma
Not transplant eligible Transplant eligible
Chemotherapy R-hyperCVAD R-CHOP
Response
< CR CR Response
Relapse Transplant Observe Transplant
Other R-thalidomide mTOR Proteosome
chemoRx inhibitor inhibitor
Fig 2. Outline of treatment approaches for patients with mantle-cell
lymphoma. Eligible patients should be encouraged to participate in clinical
trials at each phase of the disease. R-hyperCVAD, rituximab, cyclophos-
phamide, vincristine, doxorubicin, and dexamethasone; R-CHOP, rituximab,
cyclophosphamide, doxorubicin, vincristine, and prednisone; CR, complete
remission; mTOR, mammalian target of rapamycin.
JOURNAL OF CLINICAL ONCOLOGY

initial regimen, re-treated with the previously successful
therapy. The success of bortezomib, temsirolimus, and
thalidomide provides a rationale for combination with
conventional therapies in a variety of designs. Indeed, it
Author’s Disclosures of Potential Conflicts of Interest
The following author or their immediate family members indicated a financial interest. No conflict exists for drugs or
devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure
categories, or for more information about ASCO’s conflict of interest policy, please refer to the Author Disclosure Declaration
and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Author Name Employment Leadership
Thomas E. Witzig
Dollar Amount codes:
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Consultant Stock Honoraria
Wyeth Pharmaceuticals (A)
(A) ⬍ $10,000 (B) $10,000-99,999 (C) $ $100,000
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- - -
Research Fund Testimony Other
(N/R) Not Required
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