Mantle Cell Lymphoma
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Mantle cell lymphoma (MCL) is a type of
non-Hodgkin's lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tire ...
, comprising about 6% of cases. It is named for the
mantle zone The mantle zone (or just mantle) of a lymphatic nodule (or lymphatic follicle) is an outer ring of small lymphocytes surrounding a germinal center. It is also known as the "corona". It contains transient lymphocytes. It is the location of th ...
of the lymph nodes where it develops. The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991. MCL is a subtype of
B-cell lymphoma The B-cell lymphomas are types of lymphoma affecting B cells. Lymphomas are Tumors of the hematopoietic and lymphoid tissues, "blood cancers" in the lymph nodes. They develop more frequently in older adults and in immunocompromised individuals. ...
, due to CD5 positive antigen-naive pregerminal center B-cell within the mantle zone that surrounds normal
germinal center Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
follicles. MCL cells generally over-express
cyclin D1 Cyclin D1 is a protein that in humans is encoded by the ''CCND1'' gene. Gene expression The CCND1 gene encodes the cyclin D1 protein. The human CCND1 gene is located on the long arm of chromosome 11 (band 11q13). It is 13,388 base pairs lo ...
due to the t(11:14) translocation, a
chromosomal translocation In genetics, chromosome translocation is a phenomenon that results in unusual rearrangement of chromosomes. This includes "balanced" and "unbalanced" translocation, with three main types: "reciprocal", "nonreciprocal" and "Robertsonian" transloc ...
in the
DNA Deoxyribonucleic acid (; DNA) is a polymer composed of two polynucleotide chains that coil around each other to form a double helix. The polymer carries genetic instructions for the development, functioning, growth and reproduction of al ...
.


Signs and symptoms

People with mantle cell lymphoma typically present with symptoms later in life, with a median age of onset between 60 and 70 years of age. In Western countries MCL accounts for around 7% of adult non-Hodgkin's lymphomas, with between 4 and 8 per cases per million diagnosed each year. The incidence of MCL increases with age. In the United States, the median age for its diagnosis is 68 years. Three-quarters of patients are men. In addition, patients are more likely to be Caucasian. People commonly present with a non-localizing
lymphadenopathy Lymphadenopathy or adenopathy is a disease of the lymph nodes, in which they are abnormal in size or consistency. Lymphadenopathy of an inflammatory type (the most common type) is lymphadenitis, producing swollen or enlarged lymph nodes. In c ...
(enlarged lymph nodes) with
B symptoms B symptoms are a set of symptoms, namely fever, night sweats, and unintentional weight loss, that can be associated with both Hodgkin lymphoma and non-Hodgkin lymphoma. These symptoms are not specific to lymphomas, especially each one considered ...
including fevers, chills and night sweats sometimes being present. 80% of patients present with stage 3 or 4 disease (advanced disease) at the time of diagnosis, with involvement of the bone marrow, liver or gastrointestinal tract. 25% of patients present with a bulky lymphadenopathy characterized by lymph nodes greater than 10 cm in size. Other patients may present with
central nervous system The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain, spinal cord and retina. The CNS is so named because the brain integrates the received information and coordinates and influences the activity o ...
(CNS) involvement, which is associated with a very poor prognosis. However, CNS involvement is rare at diagnosis. A rare subtype, known as non-nodal mantle cell lymphoma, presents without lymph node swelling (non-nodal) with circulating lymphoma cells (leukemic presentation). This type of mantle cell lymphoma is associated with a more indolent, asymptomatic and slowly progressive course, however malignant transformation to aggressive forms is possible. Mantle cell lymphoma has been reported in rare cases to be associated with severe allergic reactions to mosquito bites. These reactions involve extensive allergic reactions to mosquito bites which range from greatly enlarged bite sites that may be painful and involve necrosis to systemic symptoms (e.g. fever, swollen lymph nodes, abdominal pain, and diarrhea), or, in extremely rare cases, to life-threatening anaphylaxis. In several of these cases, the mosquito bite allergy reaction occurred prior to the diagnosis of MCL suggesting that mosquito bite allergy can be a manifestation of early-developing mantle cell lymphoma.


Pathogenesis

MCL, like most
cancer Cancer is a group of diseases involving Cell growth#Disorders, abnormal cell growth with the potential to Invasion (cancer), invade or Metastasis, spread to other parts of the body. These contrast with benign tumors, which do not spread. Po ...
s, results from the acquisition of a combination of (non-inherited) genetic mutations in
somatic cells In cellular biology, a somatic cell (), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Somatic cells compose the body of an organism a ...
. 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 The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
gene, that contributes to the abnormal proliferation of the malignant cells. MCL cells may also be resistant to drug-induced
apoptosis Apoptosis (from ) is a form of programmed cell death that occurs in multicellular organisms and in some eukaryotic, single-celled microorganisms such as yeast. Biochemistry, Biochemical events lead to characteristic cell changes (Morphology (biol ...
, 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 (aka ''blastoid'') variants have intermediate to large-sized cells with finely dispersed
chromatin Chromatin is a complex of DNA and protein found in eukaryote, eukaryotic cells. The primary function is to package long DNA molecules into more compact, denser structures. This prevents the strands from becoming tangled and also plays important r ...
, 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

The history and physical examination may reveal some of the signs and symptoms consistent with Mantle Cell Lymphoma. Biopsy of the involved tissues (such as the lymph nodes, bone marrow, gastrointestinal tract, spleen or other areas) shows the characteristic histopathologic changes of MCL. There are distinct growth patterns of MCL seen on biopsy; these include the diffuse type, nodular type, mantle zone lymphoma and in situ mantle cell lymphoma. In the diffuse growth pattern, there is a diffuse growth of lymphoma cells throughout the lymph node resulting in effacement of the architecture of the lymph node. In the nodular type, there are large nodules of MCL cells in the lymph node with no germinal centers observed. In MCL with expansion of the mantle zone, the lymphoma cells cause expansion of the mantle zone around normal germinal centers. And in MCL in situ, the lymphoma cells are contained within the mantle zone without expansion. Histologically, the lymphoma cells in classic MCL are characterized as small to medium lymphocytes with scant cytoplasm and clumped chromatin with prominent nuclear clefts and the nucleoli are not visible. There are cytologic subtypes; the blastoid subtype, is characterized by round nuclei, fine chromatin with some distinct nucleoli. The pleomorphic subtype is characterized by nuclei that vary in size and shape with some having a cleaved form. The blastoid and pleomorphic subtypes of MCL are associated with a more aggressive course. The most common B-cell type seen in MCL is a pre-
germinal center Germinal centers or germinal centres (GCs) are transiently formed structures within B cell zone (follicles) in secondary lymphoid organs – lymph nodes, ileal Peyer's patches, and the spleen – where mature B cells are activated, prolifera ...
cell (that has not yet undergone the germinal center reaction), that is CD5,
CD20 B-lymphocyte antigen CD20 or CD20 is B lymphocyte cell-surface molecule. It is a 33-37 kDa non-glycosylated protein. CD20 is expressed on the surface of B-cells from the pre-B phase, the expression is lost in terminally differentiated plasm ...
,
CD19 B-lymphocyte antigen CD19, also known as CD19 molecule ( Cluster of Differentiation 19), B-Lymphocyte Surface Antigen B4, T-Cell Surface Antigen Leu-12 and CVID3 is a transmembrane protein that in humans is encoded by the gene ''CD19''. In human ...
positive with expression of
IgM Immunoglobulin M (IgM) is the largest of several isotypes of antibodies (also known as immunoglobulin) that are produced by vertebrates. IgM is the first antibody to appear in the response to initial exposure to an antigen; causing it to also ...
and
IgD Immunoglobulin D (IgD) is an antibody isotype that makes up about 1% of proteins in the plasma membranes of immature B-lymphocytes where it is usually co-expressed with another cell surface antibody called IgM. IgD is also produced in a secreted ...
with
monoclonal In biology, monoclonality refers to the state of a line of cells that have been derived from a single clonal origin. Thus, "monoclonal cells" can be said to form a single clone. The term ''monoclonal'' comes . The process of replication can occ ...
kappa and gamma light chains.
CD23 CD23, also known as Fc epsilon RII, or FcεRII, is the "low-affinity" biochemistry, receptor for IgE, an antibody isotype involved in allergy and resistance to parasitism, parasites, and is important in regulation of IgE levels. Unlike many of the ...
and CD200 are usually negative and cyclin-D1 (a cell cycle regulatory protein controlling transition from the
G1 phase The G1 phase, gap 1 phase, or growth 1 phase, is the first of four phases of the cell cycle that takes place in eukaryotic cell division. In this part of interphase, the cell synthesizes Messenger RNA, mRNA and proteins in preparation for subsequ ...
to the
S phase S phase (Synthesis phase) is the phase of the cell cycle in which DNA is replicated, occurring between G1 phase and G2 phase. Since accurate duplication of the genome is critical to successful cell division, the processes that occur during S ...
in the
cell cycle The cell cycle, or cell-division cycle, is the sequential series of events that take place in a cell (biology), cell that causes it to divide into two daughter cells. These events include the growth of the cell, duplication of its DNA (DNA re ...
) is classically overexpressed in MCL. SOX11 (a transcription factor controlling genes involved in cell survival) is characteristically over-expressed in MCL as well. Ki-67, a marker of cell proliferation, if elevated (greater than 30% expression) is associated with an aggressive course of MCL. Chromosomal assessment using
fluorescence in situ hybridization Fluorescence ''in situ'' hybridization (FISH) is a molecular cytogenetic technique that uses fluorescent probes that bind to only particular parts of a nucleic acid sequence with a high degree of sequence complementarity. It was developed by ...
shows the characteristic chromosomal translocation t(11;14)(q13;q32) which is present in 90–95% of cases of MCL. Imaging using
computed tomography A computed tomography scan (CT scan), formerly called computed axial tomography scan (CAT scan), is a medical imaging technique used to obtain detailed internal images of the body. The personnel that perform CT scans are called radiographers or ...
(CT) or
positron emission tomography–computed tomography The positron or antielectron is the particle with an electric charge of +1'' e'', a spin of 1/2 (the same as the electron), and the same mass as an electron. It is the antiparticle (antimatter counterpart) of the electron. When a positron coll ...
is required to assess for any extra-nodal or distal involvement.
MRI Magnetic resonance imaging (MRI) is a medical imaging technique used in radiology to generate pictures of the anatomy and the physiological processes inside the body. MRI scanners use strong magnetic fields, magnetic field gradients, and rad ...
of the brain and the spine are performed in cases of MCL with suspected central nervous system involvement. And, since 40-80% of MCL presents with gastrointestinal involvement at the time of diagnosis,
endoscopy An endoscopy is a procedure used in medicine to look inside the body. The endoscopy procedure uses an endoscope to examine the interior of a hollow organ or cavity of the body. Unlike many other medical imaging techniques, endoscopes are insert ...
(
colonoscopy Colonoscopy () or coloscopy () is a medical procedure involving the Endoscopy, endoscopic examination of the large bowel (colon) and the distal portion of the small bowel. This examination is performed using either a Charge-coupled device, CCD ...
and
esophagogastroduodenoscopy Esophagogastroduodenoscopy (EGD) or oesophagogastroduodenoscopy (OGD), also called by various other names, is a diagnostic endoscopic procedure that visualizes the upper part of the gastrointestinal tract down to the duodenum. It is considered ...
(EGD)) with biopsies may also aid in the diagnosis, but they are not always required for the diagnosis of MCL. The diagnosis may be complicated as a minority of cases of
multiple myeloma Multiple myeloma (MM), also known as plasma cell myeloma and simply myeloma, is a cancer of plasma cells, a type of white blood cell that normally produces antibody, antibodies. Often, no symptoms are noticed initially. As it progresses, bone ...
,
chronic lymphocytic leukemia Chronic lymphocytic leukemia (CLL) is a type of cancer that affects the blood and bone marrow. In CLL, the bone marrow makes too many lymphocytes, which are a type of white blood cell. In patients with CLL, B cell lymphocytes can begin to colle ...
and
plasma cell leukemia Plasma cell leukemia (PCL) is a plasma cell dyscrasia, i.e. a disease involving the malignant degeneration of a subtype of white blood cells called plasma cells. It is the terminal stage and most aggressive form of these dyscrasias, constituting ...
may also present with the t(11;14)(q13;q32) translocation. The diagnosis may be complicated further as some cases of MCL present atypically; these rare subtypes include CD10-positive MCL, CD5-negative MCL, cyclin D1-negative MCL, CD200-positive MCL, SOX-11-negative MCL, and CD23-positive MCL. The cyclin-D1-negative MCL subtypes usually result in lymphomagenesis via over-expression of
cyclin D2 G1/S-specific cyclin-D2 is a protein that in humans is encoded by the ''CCND2'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protei ...
,
cyclin D3 G1/S-specific cyclin-D3 is a protein that in humans is encoded by the ''CCND3'' gene. Function The protein encoded by this gene belongs to the highly conserved cyclin family, whose members are characterized by a dramatic periodicity in protei ...
or
cyclin E Cyclin E is a member of the cyclin family. Cyclin E binds to G1 phase Cdk2, which is required for the transition from G1 to S phase of the cell cycle that determines initiation of DNA duplication. The Cyclin E/CDK2 complex phosphorylates p27 ...
, which also lead to cell cycle hyperactivity and have a similar prognosis to the main cyclin-D1 variant of MCL. The Lugano and Ann Arbor Staging systems are two commonly used clinical staging criteria used to stage the disease, allowing decisions to be made with respect to treatment, prognosis and
salvage therapy Salvage therapy, also known as rescue therapy, is a form of therapy given after an ailment does not respond to standard therapy. The most common diseases that require salvage therapy are HIV and various cancers. The term is not clearly defined; i ...
.


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. As of 2023 it is incurable though some patients can live many years after their initial diagnosis. Regimens are available that treat relapses, and new approaches are under test. Because of the aforementioned factors, many MCL patients enroll in clinical trials to get the latest treatments – a survey at a specialist treatment centre in the UK showed that In total 58·7% of patients treated at the hospital were enrolled on at least one clinical trial. Indeed, this might well be a recommendation by the patient's care team in the hope it will give them access to the latest advances. There are four classes of treatments in general use:
chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
,
immunotherapy Immunotherapy or biological therapy is the treatment of disease by activating or suppressing the immune system. Immunotherapies designed to elicit or amplify an immune response are classified as ''activation immunotherapies,'' while immunotherap ...
,
radioimmunotherapy Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen ...
and biologic agents. The phases of treatment are generally: frontline, following diagnosis, consolidation, after frontline response (to prolong remissions), and relapse. Relapse is usually experienced multiple times.


Chemotherapy

Chemotherapy Chemotherapy (often abbreviated chemo, sometimes CTX and CTx) is the type of cancer treatment that uses one or more anti-cancer drugs (list of chemotherapeutic agents, chemotherapeutic agents or alkylating agents) in a standard chemotherapy re ...
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 Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
is the most common chemotherapy, and often given as outpatient by IV. A stronger chemotherapy with greater side effects (mostly hematologic) is HyperCVAD, often given in the hospital setting, with rituximab and generally to fitter patients (some of which are over 65). HyperCVAD is becoming popular and showing promising results, especially with rituximab. It can be used on some elderly (over 65) patients, but seems only beneficial when the baseline Beta-2-MG blood test was normal. It is showing better complete remissions (CR) and progression-free survival (PFS) than CHOP regimens. A less intensive option is
bendamustine Bendamustine, sold under the brand name Treanda among others, is a chemotherapy medication used in the treatment of chronic lymphocytic leukemia (CLL), multiple myeloma, and non-Hodgkin's lymphoma. It is given by intravenous, injection into a v ...
with rituximab. Second line treatment may include
fludarabine Fludarabine is a purine analogue and antineoplastic agent. It is generally used as its 5-O-phosphorylated form known as fludarabine phosphate, sold under the brand name Fludara among others. It is a chemotherapy medication used in the treatm ...
, combined with
cyclophosphamide Cyclophosphamide (CP), also known as cytophosphane among other names, is a medication used as chemotherapy and to suppress the immune system. As chemotherapy it is used to treat lymphoma, multiple myeloma, leukemia, ovarian cancer, breast cancer ...
and/or
mitoxantrone Mitoxantrone (INN, BAN, USAN; also known as Mitozantrone in Australia; trade name Novantrone) is an anthracenedione antineoplastic agent. Uses Mitoxantrone is used to treat certain types of cancer, mostly acute myeloid leukemia. It improves th ...
, usually with rituximab.
Cladribine Cladribine, sold under the brand name Leustatin, among others, is a medication used to treat hairy cell leukemia (formally named leukemic reticuloendotheliosis) and B-cell chronic lymphocytic leukemia. Cladribine, sold under the brand name Mav ...
and
clofarabine Clofarabine is a purine nucleoside antimetabolite marketed in the United States and Canada as Clolar. In Europe and Australia/New Zealand the product is marketed under the name Evoltra. It is FDA-approved for treating relapsed or refractory a ...
are two other medications being investigated in MCL. A relatively new regimen that uses old medications is PEP-C, which includes relatively small, daily doses of
prednisone Prednisone is a glucocorticoid medication mostly used to immunosuppressive drug, suppress the immune system and decrease inflammation in conditions such as asthma, COPD, and rheumatologic diseases. It is also used to treat high blood calcium ...
,
etoposide Etoposide, sold under the brand name Vepesid among others, is a chemotherapy medication used for the treatments of a number of types of cancer including testicular cancer, lung cancer, lymphoma, leukemia, neuroblastoma, and ovarian cancer. It is ...
, procarbazine, and cyclophosphamide, taken orally, has proven effective for relapsed patients. According to Dr. John Leonard, 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 Total body irradiation (TBI) is a form of radiotherapy used primarily as part of the preparative regimen for haematopoietic stem cell (or bone marrow) transplantation. As the name implies, TBI involves irradiation of the entire body, though in mod ...
(TBI), in an attempt to destroy all evidence of the disease. The downside to this is the destruction of the patient's entire immune system as well, requiring rescue by transplantation of a new immune system (
hematopoietic stem cell transplantation Hematopoietic stem-cell transplantation (HSCT) is the transplantation of multipotent hematopoietic stem cells, usually derived from bone marrow, peripheral blood, or umbilical cord blood, in order to replicate inside a patient and produce ...
), using either
autologous stem cell transplantation Autologous stem-cell transplantation (also called autogenous, autogenic, or autogenic stem-cell transplantation and abbreviated auto-SCT) is the autologous transplantation of stem cells—that is, transplantation in which stem cells ( undifferen ...
, or those from a matched donor (an allogeneic stem cell transplant). A presentation at the December 2007 American Society of Hematology (ASH) 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 Mantle Cell Lymphoma Network indicating that induction regimens containing monoclonal antibodies and high dose cytarabine followed by autologous stem cell transplantation should become the standard of care of MCL patients up to approximately 65 years of age. 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 Rituximab, sold under the brand name Rituxan among others, is a monoclonal antibody medication used to treat certain autoimmune diseases and types of cancer. It is used for non-Hodgkin lymphoma, chronic lymphocytic leukemia (in children and ad ...
monoclonal antibody, sold under the trade name Rituxan (or as Mabthera in Europe and Australia). 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 A monoclonal antibody (mAb, more rarely called moAb) is an antibody produced from a Lineage (evolution), cell lineage made by cloning a unique white blood cell. All subsequent antibodies derived this way trace back to a unique parent cell. Mon ...
combined with radioactive molecules known as
radioimmunotherapy Radioimmunotherapy (RIT) uses an antibody labeled with a radionuclide to deliver cytotoxic radiation to a target cell. It is a form of unsealed source radiotherapy. In cancer therapy, an antibody with specificity for a tumor-associated antigen ...
. These include Zevalin and Bexxar. Rituximab has also been used in small numbers of patients in combination with
thalidomide Thalidomide, sold under the brand names Contergan and Thalomid among others, is an oral administered medication used to treat a number of cancers (e.g., multiple myeloma), graft-versus-host disease, and many skin disorders (e.g., complication ...
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 vaccine A cancer vaccine, or oncovaccine, is a vaccine that either treats existing cancer or prevents development of cancer. Vaccines that treat existing cancer are known as ''therapeutic'' cancer vaccines or tumor antigen vaccines. Some of the vaccines ...
s,
adoptive cell transfer Adoptive cell transfer (ACT) is the transfer of cells into a patient. The cells may have originated from the patient or from another individual. The cells are most commonly derived from the immune system with the goal of improving immune functio ...
, and immunotransplant, which combines vaccination and autologous stem cell transplant. As of 2023, active immunotherapies are not currently a standard of care, but numerous
clinical trial Clinical trials are prospective biomedical or behavioral research studies on human subject research, human participants designed to answer specific questions about biomedical or behavioral interventions, including new treatments (such as novel v ...
s are ongoing.


Targeted therapy

Two Bruton tyrosine kinase inhibitors (BTKi), one In November 2013,
ibrutinib Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...
(brand name
Imbruvica Ibrutinib, sold under the brand name Imbruvica among others, is a small molecule drug that inhibits B-cell proliferation and survival by irreversibly binding the protein Bruton's tyrosine kinase (BTK). Blocking BTK inhibits the B-cell receptor ...
, Pharmacyclics LLC) and one in October 2017,
acalabrutinib Acalabrutinib, sold under the brand name Calquence, is a anti-cancer medication used to treat various types of non-Hodgkin lymphoma, including mantle cell lymphoma and chronic lymphocytic leukemia/small lymphocytic lymphoma. It may be used bo ...
(brand name Calquence, AstraZeneca Pharmaceuticals LP) were approved in the United States for treating mantle cell lymphoma. However, although these medications are beneficial their duration is short and patients typically relapse. In November 2019,
zanubrutinib Zanubrutinib, sold under the brand name Brukinsa, is an anticancer medication used for the treatment of mantle cell lymphoma (MCL), Waldenström's macroglobulinemia (WM), marginal zone lymphoma (MZL), and chronic lymphocytic leukemia (CLL). ...
(Brukinsa) was approved in the United States with an indication for the treatment of adults with mantle cell lymphoma who have received at least one prior therapy. Pirtobrutinib (Jaypirca) was approved for medical use in the United States in January 2023.


Gene therapy

Brexucabtagene autoleucel (Tecartus) was approved for medical use in the United States in July 2020, with an indication for the treatment of adults with relapsed or refractory mantle cell lymphoma. It was approved for medical use in the European Union in December 2020. Each dose of brexucabtagene autoleucel is a customized treatment created using the recipient's own immune system to help fight the lymphoma. The recipient's
T cell T cells (also known as T lymphocytes) are an important part of the immune system and play a central role in the adaptive immune response. T cells can be distinguished from other lymphocytes by the presence of a T-cell receptor (TCR) on their cell ...
s, a type of white blood cell, are collected and genetically modified to include a new gene that facilitates the targeting and killing of the lymphoma cells. These modified T cells are then infused back into the recipient.


Prognosis

Recent clinical advances in mantle cell lymphoma (MCL) have seen standard‐of‐care treatment algorithms transformed. Frontline rituximab combination therapy, high dose cytarabine‐based induction in younger patients and, more recently, Bruton Tyrosine Kinase (BTK) inhibitors in the relapse setting have all demonstrated survival advantage in clinical trials (Wang et al., 2013; Eskelund et al., 2016; Rule et al., 2016). Over the last 15 years these practices have gradually become embedded in clinical practice and real‐world data has observed corresponding improvements in patient survival (Abrahamsson et al., 2014; Leux et al., 2014). The overall
5-year survival rate The five-year survival rate is a type of survival rate for estimating the prognosis of a particular disease, normally calculated from the point of diagnosis. Lead time bias from earlier diagnosis can affect interpretation of the five-year surviva ...
for MCL is generally 50% (advanced stage MCL) to 70% (for limited-stage MCL). Prognosis for individuals with MCL is problematic and indexes do not work well because most patients present at the 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 (MIPI) 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 (median survival not reached after median 32 months follow-up and 5-year OS rate of 60%), intermediate risk (median survival 51 months) and high risk (median survival 29 months). In addition to the 4 independent prognostic factors included in the model, the cell proliferation index (Ki-67) 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 non-Hodgkin's lymphomas 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. 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. It has been suggested that in time, some non-blastic MCL transforms to blastic; however, this model has the assumption that increasing genetic alterations lead to the loss of cell cycle control, the higher proliferation rate, and thus to blastoid features. But blastoid features are frequently seen at initial presentation in some patients, whereas other cases remain morphologically stable classical MCL throughout the duration of the disease. 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 (almost 7 yrs).
Beta-2 microglobulin β2 microglobulin (B2M) is a component of MHC class I molecules. MHC class I molecules have α1, α2, and α3 proteins which are present on all nucleated cells (excluding red blood cells). In humans, the β2 microglobulin protein is encoded by t ...
is another risk factor in MCL used primarily for transplant patients. Values less than three have yielded 95% overall survival to six years for auto SCT where over three yields a median of 44 most overall survival for auto SCT (Khouri 03). This is not yet fully validated. Testing for high levels of
lactate dehydrogenase Lactate dehydrogenase (LDH or LD) is an enzyme found in nearly all living cells. LDH catalyzes the conversion of pyruvic acid, pyruvate to lactic acid, lactate and back, as it converts NAD+ to NADH and back. A dehydrogenase is an enzyme that t ...
in patients with non-Hodgkin's lymphoma is useful because it is released when body tissues break down for ''any'' reason. While it cannot be used as a sole means of diagnosing non-Hodgkin's lymphoma, it is a marker for tracking tumor burden in those diagnosed by other means. The normal range is approximately between 140 and 280 U/L but the clinical interpretation will depend upon the patient's symptoms.


Epidemiology

6% of
non-Hodgkin's lymphoma Non-Hodgkin lymphoma (NHL), also known as non-Hodgkin's lymphoma, is a group of blood cancers that includes all types of lymphomas except Hodgkin lymphomas. Symptoms include enlarged lymph nodes, fever, night sweats, weight loss, and tire ...
cases are mantle cell lymphoma. , the ratio of males to females affected is about 4:1.


See also

* ''In situ'' mantle cell lymphoma *
List of hematologic conditions :''This is an incomplete list, which may never be able to satisfy certain standards for completion.'' There are many conditions of or affecting the human hematologic system—the biological system that includes plasma, platelets, leukocytes, an ...


References


Further reading

* * *


External links

{{Portal bar , Medicine Non-Hodgkin lymphoma