Mantle Cell Lymphoma Facts
No. 4 in a series providing the latest information for patients, caregivers and
healthcare professionals
www.LLS.org
•
Information Specialist: 800.955.4572
Highlights
lMantle
cell lymphoma (MCL) is one of several
subtypes of B-cell non-Hodgkin lymphoma.
lMCL
usually begins with lymph node enlargement;
it can spread to other tissues such as the marrow
and liver.
lMCL
can sometimes begin in a lymphocyte outside
a lymph node, such as in the gastrointestinal tract.
lMCL
is distinguished by overexpression of cyclin
D1 (a protein that stimulates cell growth) in almost
all cases. The overexpression of cyclin D1 is usually
caused by a translocation between chromosomes
11 and 14.
lA
number of chemotherapy plus rituximab
(Rituxan®) combinations are used to treat MCL.
Bortezomib (Velcade®) may be used to treat patients
who have progressed disease. Clinical trials are
underway to study potential improvements in
current treatment approaches.
lAutologous
stem cell transplantation may be used
to treat MCL. Treatment with allogeneic stem cell
transplantation or reduced-intensity allogeneic
stem cell transplantation may be beneficial for some
patients, based on a medical evaluation and the
availability of a matched related stem cell donor.
Introduction
Lymphoma is the general name for many related subtypes of
cancer that arise in the lymphocytes (white blood cells).
Lymphoma is divided into two major categories: Hodgkin
lymphoma (HL) and non-Hodgkin lymphoma (NHL).
Mantle cell lymphoma (MCL) is one of several subtypes
of NHL.
Lymphoma may arise in any one of three types of
lymphocytes: B lymphocytes (B cells), T lymphocytes
(T cells) and natural killer (NK) cells. B lymphocytes make
antibodies to fight infection; T lymphocytes have many
functions, including helping B lymphocytes make the
antibodies that fight infection; and natural killer cells attack
cancer cells and viruses. B-cell lymphomas are more
common than T-cell lymphomas. Most lymphocytes are
found in the lymphatic system, the major part of the body’s
immune system. The lymphatic system consists of a
network of organs, including the spleen, the lymph nodes
(small bean-shaped structures located throughout the body),
the lymphatic vessels and areas in the gastrointestinal tract.
This fact sheet includes information about the diagnosis and
management of MCL. It also provides specific information
on the stages and treatment of the disease, new treatments
undergoing investigation and support resources. For
additional free information about NHL subtypes, please see
The Leukemia & Lymphoma Society (LLS) publications
Non-Hodgkin Lymphoma and The Lymphoma Guide:
Information for Patients and Caregivers.
About Mantle Cell Lymphoma
Mantle cell lymphoma (MCL) results from a malignant
transformation of a B lymphocyte in the outer edge of a
lymph node follicle (the mantle zone). The transformed
B lymphocyte grows in an uncontrolled way and the
accumulated lymphoma cells form tumors in lymph nodes,
which leads to their enlargement. The MCL cells can enter
the lymphatic channels and the blood, and can spread to
other lymph nodes or tissues, such as the marrow, liver and
gastrointestinal tract.
There are about 66,360 new cases of NHL in the United
States each year. MCL patients represent about 6 percent of
all new cases of NHL per year. MCL occurs more frequently
in older adults—the average age-range at diagnosis is the
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Revised July 2012
Mantle Cell Lymphoma Facts
mid-60s; it is more often diagnosed in males than in
females; and white males and females are at a higher risk
than black males and females for an MCL diagnosis.
Causes
About 85 percent of patients with MCL have a genetic
change of developing B lymphocytes that involves
chromosome 11 and chromosome 14. This is called a
“reciprocal translocation,” and is abbreviated as t(11;14).
As a result, short segments of chromosome 11 and
chromosome 14 exchange places. The exchange occurs at
the site of the cyclin D1 gene on chromosome 11 and the
site of a gene that controls the formation of antibody
molecules on chromosome 14. The t(11;14) triggers an
overproduction of cyclin D1, a protein that supports and
directs cell division and growth. The overproduction of the
cyclin D1 protein leads to masses (tumors) of transformed
lymphocytes (MCL cells). In a sense, this translocation
can be thought of as the cause of the disease, possibly
independent of the effects of another factor.
In a small proportion of patients t(11;14) is not present.
In most of these patients, other genetic changes cause excess
production of cyclin D1. Rarely, MCL arises from
overexpression of other cyclin genes (e.g., cyclin D2 and
cyclin D3).
Signs, Symptoms and Complications
Most patients with MCL have disease involving multiple
lymph nodes and other sites of the body. These sites may
include the spleen, marrow and blood, the lymph nodes
in the throat (tonsils and adenoids), the liver or the
gastrointestinal tract. MCL cells may enter the brain,
lungs and spinal cord.
Patients who have MCL may experience loss of appetite and
weight loss, fever, night sweats, nausea and/or vomiting,
indigestion, abdominal pain or bloating, a feeling of
“fullness” or discomfort due to an enlarged tonsils, liver or
spleen, pressure or pain in the lower back often extending
down one or both legs, or fatigue due to developing anemia.
Disease complications from disease progression may include
lCytopenias
(neutropenia [low white blood cell counts],
anemia [low red blood cell counts] and/or
thrombocytopenia [low numbers of platelets]) because
the MCL is in the bone marrow.
l
Gastrointestinal,
pulmonary, or central nervous system
(CNS) complications because the MCL is extranodal
(outside the lymph nodes and in organs). In the
gastrointestinal tract a condition known as “multiple
small-intestine polyps” may result from the lymphoma
cell growth.
l
Leukocytosis
(high white blood cell counts) in the event
of progression to the leukemia phase of the disease.
Diagnosis
A patient with a potential diagnosis of lymphoma needs to
make sure that his or her subtype has been correctly
identified. Treatment depends on knowing the specific
diagnosis. Each patient should be evaluated by a
hematologist/oncologist who specializes in treating patients
who have NHL.
Lymphomas are diagnosed by the examination of
affected tissue, obtained from a surgical biopsy, usually of
a lymph node. Cells obtained from a fine needle aspiration
are not enough to establish a diagnosis.
Microscopic examination of tissue from the lymph node
biopsy can determine that lymphoma is present. A
diagnosis of MCL is made if additional examination of
the tissue shows that the lymphoma cells
lHave
surface markers of B cells
lOverexpress
lContain
the cyclin D1 protein within the cells
the translocation 11;14.
Blood tests and imaging scans may also be done.
A hematopathologist (a doctor who specializes in examining
tissue and diagnosing disease) will determine if the MCL
is the common type (found in most patients) or a blastoid
variant. In the blastoid variant, the cells are bigger; they
grow and divide more rapidly, are more aggressive and more
challenging to treat. The blastoid variant of MCL may be
present at diagnosis or may emerge over time.
Treatment Planning
Many doctors who care for MCL patients use The Mantle
Cell International Prognostic Index (MIPI) to help plan
treatment. This index uses four independent prognostic
factors that may correlate with prognosis. The factors are:
age, performance status (ability to perform activities of daily
life), LDH (lactate dehydrogenase) levels and leukocyte
(white blood cell) count. Patients are assigned to a low-risk,
intermediate-risk or high-risk category based on the number
of points alloted to each factor.
In addition, doctors stage MCL to help them assess the
extent of the disease and decide on the best treatment plan.
Staging is described in the next section.
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Mantle Cell Lymphoma Facts
Your treatment team may include more than one
specialist. It is important for you and members of your
medical team to discuss all treatment options,
including treatments being studied in clinical trials.
Figure 1. Lymphoma Stages
STAGE I
For more information about choosing a doctor or a
treatment center, see the free LLS publication Choosing a
Blood Cancer Specialist or Treatment Center.
One lymph node region
or a single organ.
Staging
Diaphragm
Some tests that are useful in determining the extent of disease
(staging) include
lComplete
blood cell counts, to assess the concentration
of red cells, white cells and platelets
lBone
marrow aspiration and biopsy, to determine
whether or not the disease has extended beyond the
lymph nodes and into the marrow
l
Imaging
studies, including computed tomography (CT)
scans of the chest, abdomen and pelvis, to see whether
the disease is present in the deep lymph nodes, liver,
spleen or in other parts of the body (see Figure 1)
to check levels of specific proteins in
the blood, especially measurements of serum lactic
dehyrogenase (LDH) and beta2-microglobulin, because
these are indirect markers of disease extent and rate of
progression.
Diaphragm
STAGE II
Two or more lymph node
regions on the same side of
the diaphragm.
lStudies
For additional information about laboratory and imaging
tests, see the free LLS publication Understanding Lab and
Imaging Tests.
STAGE III
Two or more lymph node
regions above and below
the diaphragm.
Diaphragm
Diaphragm
STAGE IV
Widespread disease in
lymph nodes and/or other
parts of the body.
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Mantle Cell Lymphoma Facts
Treatment
Most MCL patients receive treatment following diagnosis
and staging. For a small number of patients who have
slow-growing (indolent) MCL and are otherwise well,
doctors may recommend a period of close observation,
also called “watchful waiting,” before treatment is started.
In these cases, the doctor will want to see the patient every
2 to 3 months, and do imaging tests done every 3 to 6
months. For patients with indolent MCL, therapy begins
when symptoms become troublesome or there are signs of
progression (for example, increasing lymph node size or
new enlarged nodes).

More intensive combinations include the following:




Patients who are have symptoms at diagnosis are not
appropriate candidates for watchful waiting, since prompt
treatment typically resolves symptoms.
For more aggressive disease, for instance, if the disease has
spread to the central nervous system, drugs may be
administered directly into the fluid bathing the spinal canal.
This is referred to as “intrathecal therapy.”
A number of chemotherapy and rituximab (Rituxan®)
combinations (see below) are used to treat patients who
have MCL. Rituxan is a approved by the US Food and
Drug Administration (FDA) to treat NHL and certain
other diseases. It is monoclonal antibody, made in the
laboratory that targets and destroys cells with the CD20
antigen, including MCL cells. A number of studies show
that patients who are treated with chemotherapy plus
Rituxan have a higher initial response rate than the reponse
rate achieved with chemotherapy alone.
Types of Treatment
Combination Therapies. Less intensive combinations
include the following:




R
-CHOP [Rituxan, cyclophosphamide,
hydroxydaunomycin (doxorubicin), Oncovin®
(vincristine), and prednisone]
M
odified R-hyperCVAD [Rituxan,
cyclophosphamide, vincristine, doxorubicin
(Adriamycin®), and dexamethasone alternating with
high-dose cytarabine and methotrexate] either with or
without autologous stem cell transplantation
R
-CHOP [Rituxan, cyclophosphamide,
hydroxydaunomycin (doxorubicin), Oncovin®
(vincristine), and prednisone] plus
radioimmunotherapies (see Treatments Under
Investigation on page 5)
R
-FCM [Rituxan, fludarabine (Fludara®),
cyclophosphamide and mitoxantrone]
B+R [bendamustine (Treanda®) and Rituxan]
R-CHOP [Rituxan, cyclophosphamide,
hydroxydaunomycin (doxorubicin), Oncovin®
(vincristine), and prednisone] with an autologous
stem cell transplantation
R-hyperCVAD [Rituxan, cyclophosphamide,
vincristine, doxorubicin (Adriamycin®), and
dexamethasone alternating with high-dose cytarabine
and methotrexate]
R-hyperCVAD [Rituxan, cyclophosphamide,
vincristine, doxorubicin (Adriamycin®), and
dexamethasone alternating with high-dose cytarabine
and methotrexate] either with or without autologous
stem cell transplantation
R-DHAP [Rituxan, dexamethasone, cytarabine and
cisplatin].
Knowing how a medication is administered can help
patients prepare for their treatments. The following drugs
from the listed combinations above are given intravenously
(IV): Rituxan, doxorubicin, vincristine, fludarabine,
mitoxantrone and cisplatin. Cyclophosphamide can be
given either intravenously or by mouth. Prednisone,
dexamethasone and methotrexate are given by mouth.
Cytarabine can be given intravenously or by intramuscular
or subcutaneous injection.
More intensive chemotherapy treatments, such as
hyperCVAD, may increase response rates, but these
treatments can be very toxic and are typically reserved for
healthier, often younger patients. However, younger
patients may want to opt for a less intensive approach. For
older, less fit patients, less intensive approaches are currently
the only options. Single use of chlorambucil may be good
for elderly patients or patients with serious comorbidities. A
study of the drug combination Treanda and Rituxan showed
that this combination is more effective and less toxic than
the standard CHOP regimen and should be considered as
initial treatment for elderly patients with MCL.
The side effects of combination treatment will depend on
many factors, including the type of treatment and dosage,
the age of the patient and coexisting medical conditions.
Therapy may induce fever or chills, fatigue, nausea,
peripheral neuropathy (tingling, burning, numbness or
pain in the hands or feet), changes in blood cell counts,
infection, skin reactions, diarrhea, shortness of breath,
temporary loss of hair and other side effects. Patients may
be less fertile after undergoing certain cancer treatments.
Stem Cell Transplantation. High-dose drug therapy and
autologous stem cell transplantation (a procedure involving
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Mantle Cell Lymphoma Facts
the harvesting of the patient’s own stem cells, freezing the
collection, then returning it to the patient after he or she
has received intensive drug therapy) has resulted in high
rates of clinical remission for MCL patients when used
after first remission. Older patients who are in excellent
physical condition are candidates for autologous stem cell
transplantation. Autologous transplantation combined with
R-CHOP may offer a longer remission and be an option for
some younger patients.
Allogeneic stem cell transplantation is the transfer of stem
cells from a donor to the patient following high-dose
chemotherapy or radiation therapy. This type of transplant
is determined by the patient’s medical indications and
availability of a suitable donor. There is no specific age
cutoff for stem cell transplantation. Allogeneic stem cell
transplantation is not commonly used to treat lymphoma
patients, but is sometimes used to treat MCL patients.
Reduced-intensity allogeneic transplantation may be an
option for older patients. For more information, see the
free LLS publication Blood and Marrow Stem Cell
Transplantation.
Talk to Your Doctor About Side Effects of Treatment.
Side-effects management is important. If you are having
any concerns about your side effects, talk to your doctor to
get help. Most side effects can be managed with treatment
that will not compromise treatment for your disease. In
addition, most side effects are temporary and resolve when
treatment is completed.
Some of the side effects of specific drugs are discussed on
page 4. For additional drug information, see the free LLS
publication Understanding Drug Therapy and Managing Side
Effects and the Food and Drug Administration (FDA) drug
information webpage at
www.fda.gov/drugs/resourcesforyou/consumers/default.htm.
Also, see Treatments Under Investigation on this page.
Treatment for Patients with Relapsed
and/or Refractory MCL
If a patient’s MCL returns, there are a number of different
treatment options. For patients with relapsed MCL (return
of the cancer), an allogeneic stem cell transplant may be an
option. For patients with refractory MCL (the cancer resists
treatment), a patient may try a chemotherapyregimen that
was not used previously.
For a listing of investigational agents currently being studied
for relapsed and refractory MCL patients, please see
Treatments Under Investigation.
Treatments Under Investigation
Research for MCL over the last several years has
resulted in better treatment options for patients; new
therapies are constantly emerging. Patients may have the
opportunity to take part in clinical trials. These trials,
conducted under rigorous guidelines, help clinicians and
researchers to determine the beneficial and adverse effects
of potential new treatments. Studies are also conducted to
evaluate new indications for therapies that are already
approved for other diseases. In addition, research to define
predictive biomarkers to better identify MCL subtypes
will help guide treatment decisions in the future, thereby
improving patient outcomes.
LLS is funding MCL research to study the role of the B-cell
antigen receptor in MCL, novel proteasome inhibitors to
treat MCL and other new therapies. For more information
about clinical trials, see the free LLS publication
Understanding Clinical Trials for Blood Cancers, visit
www.LLS.org/clinicaltrials or call our Information
Specialists.
Some classes of novel therapies and drugs under
investigation include
l
Cell
cycle inhibitors–Drugs of this type interfere with
the cell division process that enables tumors to grow. A
treatment that is being studied is called PD-0332991.
l
Tyrosine
kinase inhibitors–These drugs flip switches on
the pathways of the cells that are important to the cell
staying alive. Oral drugs that are being studied include a
PI3 kinase inhibitor GS-1101 (CAL-101) and Bruton’s
tyrosine kinase inhibitor ibrutinib (PCI-32765).
l
Monoclonal
antibodies–These agents provide a type of
targeted therapy directed at specific proteins. A number
of new monoclonal antibodies are being investigated
including bevacizumab (Avastin®), FDA approved for
other types of cancer and being studied in combination
with R-CHOP for untreated MCL; alemtuzumab
(Campath®), an anti-CD52 agent and FDA approved
for the treatment of chronic lymphocytic leukemia,
which is being used as part of a conditioning regimen in
allogeneic transplantation; and epratuzumab, an
anti-CD22.
l
Maintenance
Treatment–Patients who receive initial
treatment with Rituxan, plus chemotherapy and then
receive maintenance Rituxan may stay in remission
longer than if they do not continue on Rituxan. One
study of elderly patients who had responded to
induction treatment, but were not able to receive
chemotherapy and an autologous stem cell transplant,
showed their duration of remission doubled after a
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Mantle Cell Lymphoma Facts
period of maintenance Rituxan. Rituxan is also being
studied as a maintenance therapy following combination
chemotherapy to prolong response duration in patients
with recurring or refractory MCL. Clinical trials are
underway to continue to evaluate this treatment approach.
l
Proteasome
inhibitors–These drugs affect cell
pathways by blocking the activity of proteins that
are needed for cell growth and survival. Bortezomib
(Velcade®) is being studied together with Rituxan and
combination chemotherapy (R-EPOCH [Rituxan plus
etoposide, prednisone, vincristine (Oncovin®),
cyclophosphamide, hydroxydaunomycin (doxorubicin)],
R-CHOP or R-hyperCVAD) in both untreated and
refractory MCL.
l
Vaccines–Custom-made
cancer vaccines, such as
BiovaxID®, are patient-specific vaccines that do not
prevent the disease but may stimulate the immune system’s
attack on remaining MCL cells after initial therapy.
l
Stem
cell transplantation–Reduced-intensity
allogeneic stem cell transplantation, which uses less
intensive conditioning therapy prior to transplanting
donor cells is being compared to a standard allogeneic
transplantation, and the results are being studied. Some
patients showed prolonged disease-free survival.
l
mTOR
inhibitors–Agents that may work to slow or
inhibit MCL by downregulating (reducing) cell
expression of cyclin D1. They have demonstrated
activity in MCL either alone or in combination with
other therapies. Examples of mTOR inhibitors currently
under investigation include


Temsirolimus (Torisel®) for relapsed mantle cell
lymphoma. This agent is also being studied in
combination with Rituxan® and bendamustine
(Treanda®).
Everolimus (Afinitor®) is being studied in patients
with advanced, refractory or relapsed MCL. This is
also being studied in combination with lenalidomide
(Revlimid®) and as a single agent in older patients.
l
An
alkylating agent–Bendamustine (Treanda®) is FDA
approved to treat chronic lymphocytic leukemia (CLL)
and indolent B-cell NHL that has progressed during
or within six months of treatment with Rituxan or a
Rituxan-containing regimen. This drug is being studied
in combination with Rituxan and temsirolimus in
patients with relapsed MCL and Rituxan and Revlimid
in older patients who are previously untreated.
l
Immunomodulators–Thalidomide
(Thalomid®) and
Revlimid are both FDA approved to treat myeloma.
They act by modulating the immune system and by
blocking the growth of blood vessels that allow cancer
cells to grow (antiangiogenesis).These drugs are being
studied in combination with Rituxan and/or other
agents in patients with relapsed or refractory MCL or
patients who are previously untreated.
l
Radioimmunotherapy
(RIT)–Radioisotope particles
can be combined with a monoclonal antibody and other
treatments to enhance its effectiveness. The radioactive
compound attaches to the antibody and the radiation
destroys neighboring cancer cells. Tositumomab iodine
I-131-tositumomab (Bexxar®) and Yttrium-90
ibritumomab tiuxetan (Zevalin®), both given
intravenously (IV), are FDA approved to treat some
forms of NHL and are being studied for the treatment
of MCL.
A series of small molecules targeting cell death are being
tested to treat MCL. Some of these investigational agents
include: flavopiridol, an inhibitor of cyclin D1 kinases and
oral suberoylanilide hydroxamic acid (SAHA), a new class
of antitumor agents.
Treatment Outcomes
There has been noteworthy progress in the treatment of
MCL over the last decades with a near doubling of overall
survival, even though relapses are still common. Most
patients respond well to initial chemotherapy (with or
without stem cell transplantation). However, for most
patients, the disease eventually progresses or returns.
Treatment resistance may develop, which means that
a patient may become less responsive to chemotherapy.
The median progression-free period for patients with MCL is
20 months and the median overall survival is between 5 and 7
years. The prognosis for the blastoid variant of MCL is poor.
This type of MCL typically progresses after chemotherapy
treatment; better treatments are needed. Improvements in
therapy take several years of observation to determine the
results of these new approaches to treatment. Researchers
continue to look for therapies that will prolong remissions and
extend survival in patients with MCL. Outcome data cannot
determine how any one person will respond. Talk to your
doctor for more information.
Acknowledgement
LLS gratefully acknowledges
Brad S. Kahl, MD
Associate Professor of Medicine
Director of UW Lymphoma Service
Clinical Research Director for Hematologic Malignancies
University of Wisconsin Paul P. Carbone Comprehensive
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Mantle Cell Lymphoma Facts
Cancer Center
Madison, WI
for his review of Mantle Cell Lymphoma Facts and for his
important contributions to the material presented in this
publication.
We’re Here to Help
LLS is the world’s largest voluntary health organization
dedicated to funding blood cancer research, education and
patient services. LLS has chapters throughout the country
and in Canada. To find the chapter nearest you, enter your
ZIP code into “Find your Chapter” at www.LLS.org or
contact
The Leukemia & Lymphoma Society
1311 Mamaroneck Avenue
White Plains, NY 10605
Information Specialists: (800) 955-4572
Email: [email protected]
Callers may speak directly with an Information Specialist
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or by sending an email. Information Specialists can answer
general questions about diagnosis and treatment options,
offer guidance and support and assist with clinical-trial
searches for leukemia, lymphoma, myeloma,
myelodysplastic syndromes and myeloproliferative
neoplasms. The LLS website has information about how
to find a clinical trial, including a link to TrialCheck®, a
clinical-trial search service.
LLS also provides free publications that can be ordered via
the 800 number or through the “Free Education Materials”
option at www.LLS.org/resourcecenter.
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Mantle Cell Lymphoma Facts
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regard to the subject matter covered. It is distributed as a public service by
The Leukemia & Lymphoma Society (LLS), with the understanding that
The Leukemia & Lymphoma Society is not engaged in rendering medical or
other professional services.
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