Mantle cell lymphoma is one of the rarest of the non-Hodgkin's lymphomas, comprising
about 6% of NHL cases. There are only about 15,000 patients presently in the U.S. MCL
is difficult to treat and seldom considered cured. Median survival times were about 3
years, but are now estimated as approaching 6 years for new patients.
MCL is a subtype of B-cell lymphoma, due to CD5 positive antigen-naive pregerminal center
B-cell within the mantle zone that surrounds normal germinal center follicles. MCL cells
generally over-express cyclin D1 due to a t(11:14) chromosomal translocation in the
DNA. More specifically, the translocation is at t(11;14)(q13;q32).
Symptoms At diagnosis, patients typically are in their
60s and present to their physician with advanced disease. About half have either fever, night
sweats, or unexplained weight loss. Enlarged lymph nodes or splenomegaly are usually present.
Bone marrow, liver and GI tract involvement occurs relatively early in the course of the
disease. Pathogenesis
MCL, like most malignancies, results from the acquisition of a combination of genetic
mutations in somatic cells. This leads to a clonal expansion of malignant B lymphocytes.
The factors that initiate the genetic alterations are typically not identifiable, and usually
occur in people with no particular risk factors for lymphoma development. Because it is an
acquired genetic disorder, MCL is neither communicable nor inheritable. A defining characteristic
of MCL is mutation and overexpression of cyclin D1, a cell cycle gene, that contributes to
the abnormal proliferation of the malignant cells. MCL cells may also be resistant to
drug induced apoptosis, making them harder to cure with chemotherapy or radiation. Cells
affected by MCL proliferate in a nodular or diffuse pattern with two main cytologic variants:
typical or blastic. Typical cases are small to intermediate sized cells with irregular
nuclei. Blastic variants have intermediate to large sized cells with finely dispersed
chromatin and are more aggressive in nature. The tumor cells accumulate in the lymphoid
system, including lymph nodes and the spleen, with non-useful cells eventually rendering
the system dysfunctional. MCL may also replace normal cells in the bone marrow, which impairs
normal blood cell production. Diagnosis
Diagnosis generally requires stained slides of a surgically removed part of a lymph node.
Other methods are also commonly used, including cytogenetics and fluorescence in situ hybridization.
Polymerase chain reaction and CER3 clonotypic primers are additional methods, but are less
often used. The immunophenotype profile consists of CD5+,
CD10-/+,It is usually CD5+ and CD10-. CD20+, CD23-/+. Generally, cyclin D1 is expressed
but it may not be required. The workup for Mantle cell lymphoma is similar to the workup
for many indolent lymphomas and certain aggressive lymphomas.
Mantle cell lymphoma is a systemic disease with frequent involvement of the bone marrow
and gastrointestinal tract. There is also a not-uncommon leukemic phase, marked by presence
in the blood. For this reason, both the peripheral blood and bone marrow are evaluated for the
presence of malignant cells. Chest, abdominal, and pelvic CT scans are routinely performed.
Since mantle cell lymphoma may present a lymphomatous polyposis coli and colon involvement is common,
colonoscopy is now considered a routine part of the evaluation. Upper endoscopy and neck
CT scan may be helpful in selected cases. In some patients with the blastic variant,
lumbar puncture is done to evaluate the spinal fluid for involvement.
Key diagnostics for MCL CT Scan - Computerized tomography scan yields
images of part or whole body. Gives a large number of slices on X-ray image.
PET Scan - Generally of the whole body, shows a three-dimensional image of where previously
injected radioactive glucose is metabolized at a rapid rate. Faster-than-average metabolism
shows as a black area and indicates that cancer is likely present. Metabolism of radioactive
glucose may give a false positive, particularly if the patient has exercised before the test.
PET scans are much more effective when the information from them is integrated with that
from a CT scan to show more precisely where the cancer activity is located and to more
accurately measure the size of tumors. Prognosis
The overall 5-year survival rate for MCL is generally 50% to 70%.
Prognosis for individuals with MCL is problematic and indexes do not work as well due to patients
presenting with advanced stage disease. Staging is used but is not very informative, since
the malignant B-cells can travel freely though the lymphatic system and therefore most patients
are at stage III or IV at diagnosis. Prognosis is not strongly affected by staging in MCL
and the concept of metastasis does not really apply.
The Mantle Cell Lymphoma International Prognostic Index was derived from a data set of 455 advanced
stage MCL patients treated in series of clinical trials in Germany/Europe. Of the evaluable
population, approximately 18% were treated with high-dose therapy and stem cell transplantation
in first remission. The MIPI is able to classify patients into three risk groups: low risk,
intermediate risk and high risk. In addition to the 4 independent prognostic factors included
in the model, the cell proliferation index was also shown to have additional prognostic
relevance. When the Ki67 is available, a biologic MIPI can be calculated.
MCL is one of the few NHLs that can cross the boundary into the brain, yet it can be
treated in that event. There are a number of prognostic indicators
that have been studied. There is not universal agreement on their importance or usefulness
in prognosis. Ki-67 is an indicator of how fast cells mature
and is expressed in a range from about 10% to 90%. The lower the percentage, the lower
the speed of maturity, and the more indolent the disease. Katzenberger et al. Blood 2006;107:3407
graphs survival versus time for subsets of patients with varying Ki-67 indices. He shows
median survival times of about one year for 61-90% Ki-67 and nearly 4 years for 5-20%
Ki-67 index. MCL cell types can aid in prognosis in a subjective
way. Blastic is a larger cell type. Diffuse is spread through the node. Nodular are small
groups of collected cells spread through the node. Diffuse and nodular are similar in behavior.
Blastic is faster growing and it is harder to get long remissions. Some thought is that
given a long time, some non-blastic MCL transforms to blastic. Although survival of most blastic
patients is shorter, some data shows that 25% of blastic MCL patients survive to 5 years.
That is longer than diffuse type and almost as long as nodular.
Beta-2 microglobulin is another risk factor in MCL used primarily for transplant patients.
Values less than 3 have yielded 95% overall survival to 6 yrs for auto SCT where over
3 yields a median of 44 mos overall survival for auto SCT. This is not yet fully validated.
Testing for high levels of LDH in NHL patients is useful because LDH is released when body
tissues break down for any reason. While it cannot be used as a sole means of diagnosing
NHL, it is a surrogate for tracking tumor burden in those diagnosed by other means.
The normal range is approximately 100-190. Treatments
There are no proven standards of treatment for MCL, and there is no consensus among specialists
on how to treat it optimally. Many regimens are available and often get good response
rates, but patients almost always get disease progression after chemotherapy. Each relapse
is typically more difficult to treat, and relapse is generally faster. Fortunately,
regimens are available that will treat relapse, and new approaches are under test. Because
of the aforementioned factors, many MCL patients enroll in clinical trials to get the latest
treatments. There are four classes of treatments currently
in general use: chemotherapy, immune based therapy, radioimmunotherapy and new biologic
agents. The phases of treatment are generally: frontline, following diagnosis, consolidation,
after frontline response, and relapse. Relapse is usually experienced multiple times.
Chemotherapy Chemotherapy is widely used as frontline treatment,
and often is not repeated in relapse due to side effects. Alternate chemotherapy is sometimes
used at first relapse. For frontline treatment, CHOP with rituximab is the most common chemotherapy,
and often given as outpatient by IV. A stronger chemotherapy with greater side effects is
HyperCVAD, often given as in-patient, with rituximab and generally to fitter patients.
HyperCVAD is becoming popular and showing promising results, especially with rituximab.
It can be used on some elderly patients, but seems only beneficial when the baseline Beta-2-MG
blood test was normal. It is showing better complete remissions and progression free survival
than CHOP regimens. Another chemotherapy class is fludarabine monotherapy, sometimes combined
with cyclophosphamide and mitoxantrone, usually with rituximab. Cladribine and clofarabine
are two other drugs being investigated in MCL. Cytotoxic chemotherapies, including bendamustin,
are being studied alone and with similar combinations. A relatively new regimen that uses old drugs
is PEP-C, which includes relatively small, daily doses of prednisone, etoposide, procarbazine,
and cyclophosphamide, taken orally, has proven effective for relapsed patients. According
to John Leonard M.D., a key researcher/proponent of PEP-C, may have anti-angiogenetic properties,
something that he and his colleagues are testing through an ongoing drug trial.
Another approach involves using very high doses of chemotherapy, sometimes combined
with total body irradiation, in an attempt to destroy all evidence of the disease. The
downside to this is the destruction of the patients' entire immune system as well, requiring
rescue by transplantation of a new immune system, using either ones' own previously
treated and stored stem cells, or those from a matched donor. A presentation at the December
2007 American Society of Hematology conference by Christian Geisler, chairman of the Nordic
Lymphoma Group, claimed that according to trial results, mantle cell lymphoma is potentially
curable with very intensive chemo-immunotherapy followed by a stem cell transplant, when treated
upon first presentation of the disease. These results seem to be confirmed by a large
trial of the European Mantel Cell Lymphoma Network indicating that induction regimens
containing monoclonal antibodies and high dose ARA-C followed by ASCT should become
the new standard of care of MCL patients up to approximately 65 years.
A study released in April, 2013 showed that patients with previously untreated indolent
lymphoma, bendamustine plus rituximab can be considered as a preferred first-line treatment
approach to R-CHOP because of increased progression-free survival and fewer toxic effects.
Immunotherapy Immune-based therapy is dominated by the use
of the rituximab monoclonal antibody, sold under the trade name Rituxan. Rituximab may
have good activity against MCL as a single agent, but it is typically given in combination
with chemotherapies, which prolongs response duration. There are newer variations on monoclonal
antibodies combined with radioactive molecules known as Radioimmunotherapy. These include
Zevalin and Bexxar. Rituximab has also been used in small numbers of patients in combination
with thalidomide with some effect. In contrast to these antibody-based 'passive' immunotherapies,
the field of 'active' immunotherapy tries to activate a patient's immune system to specifically
eliminate their own tumor cells. Examples of active immunotherapy include cancer vaccines,
adoptive cell transfer, and immunotransplant, which combines vaccination and autologous
stem cell transplant. Though no active immunotherapies are currently a standard of care, numerous
clinical trials are ongoing. Targeted therapy
In November 2013 Ibrutinib was approved by the US FDA for treating MCL. Other targeted
agents include the proteasome inhibitor Bortezomib, mTor inhibitors such as temsirolimus, and
the P110δ inhibitor GS-1101. Epidemiology
Of all cancers involving the same class of blood cell, 6% of cases are mantle cell lymphoma.
The ratio of males to females affected is about 4:1.
See also List of hematologic conditions
References
External links A Brief Review of the Biology and Pathophysiology
of Mantle Cell Lymphoma Mantle Cell Lymphoma Consortium
Lymphoma Association – Specialist UK charity providing free information and support to
patients, their families, friends and carers