View source for Mantle cell lymphoma

{{Short description|Type of blood cancer}}
{{Use dmy dates|date=August 2023}}
{{Infobox medical condition (new)
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| image           = Mantle cell lymphoma - intermed mag.jpg
| caption         = [[Micrograph]] showing mantle cell lymphoma (bottom of image) in a [[biopsy]] of the [[terminal ileum]]. [[H&E stain]].
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| field           = [[Hematology]] and [[oncology]]
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'''Mantle cell lymphoma''' ('''MCL''') is a type of [[Non-Hodgkin lymphoma|non-Hodgkin's lymphoma]], comprising about 6% of cases.<ref>{{cite web|url=http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf|title=Mantle Cell Lymphoma Facts|website=lls.org|access-date=10 April 2018|archive-date=9 February 2015|archive-url=https://web.archive.org/web/20150209200626/http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf|url-status=dead}}</ref><ref name="Skarbnik2015">{{cite journal |vauthors=Skarbnik AP, Goy AH |title=Mantle cell lymphoma: state of the art |journal=Clin Adv Hematol Oncol |volume=13 |issue=1 |pages=44–55 |date=January 2015 |pmid=25679973 }}</ref>  It is named for the [[mantle zone]] of the lymph nodes where it develops.<ref>{{Cite web |title=Mantle cell lymphoma |url=https://www.cancerresearchuk.org/about-cancer/non-hodgkin-lymphoma/types/mantle-cell |access-date=2023-10-08 |website=www.cancerresearchuk.org |language=en}}</ref><ref>{{Cite web |date=2021-02-26 |title=Lymphoma Action {{!}} Mantle cell lymphoma |url=https://lymphoma-action.org.uk/types-lymphoma-non-hodgkin-lymphoma/mantle-cell-lymphoma |access-date=2023-10-08 |website=Lymphoma Action |language=en}}</ref> The term 'mantle cell lymphoma' was first adopted by Raffeld and Jaffe in 1991.<ref name=":3">{{Cite journal |last1=Huang |first1=Zoufang |last2=Chavda |first2=Vivek P. |last3=Bezbaruah |first3=Rajashri |last4=Dhamne |first4=Hemant |last5=Yang |first5=Dong-Hua |last6=Zhao |first6=Hong-Bing |date=2023-03-31 |title=CAR T-Cell therapy for the management of mantle cell lymphoma |journal=Molecular Cancer |volume=22 |issue=1 |pages=67 |doi=10.1186/s12943-023-01755-5 |pmid=37004047 |pmc=10064560 |issn=1476-4598 |doi-access=free }}</ref>

MCL is a subtype of [[B-cell lymphoma]],<ref>{{Cite journal |last=Shah |first=Nirav N. |last2=Colina |first2=Alfredo S. |last3=Johnson |first3=Bryon D. |last4=Szabo |first4=Aniko |last5=Furqan |first5=Fateeha |last6=Kearl |first6=Tyce |last7=Schneider |first7=Dina |last8=Vargas-Cortes |first8=Marlenny |last9=Schmeling |first9=Jessica L. |last10=Dwinell |first10=Michael B. |last11=Palen |first11=Katie |last12=Longo |first12=Walter |last13=Hematti |first13=Peiman |last14=Zamora |first14=Anthony E. |last15=Hari |first15=Parameswaran |date=2025-03-31 |title=Phase I/II Study of Adaptive Manufactured Lentiviral Anti-CD20/Anti-CD19 Chimeric Antigen Receptor T Cells for Relapsed, Refractory Mantle Cell Lymphoma |url=https://ascopubs.org/doi/10.1200/JCO-24-02158 |journal=Journal of Clinical Oncology |volume=0 |issue=0 |pages=JCO–24–02158 |doi=10.1200/JCO-24-02158 |issn=0732-183X|url-access=subscription }}</ref> due to [[CD5 (protein)|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 the [[t(11:14) translocation]],<ref>{{cite web|url=http://atlasgeneticsoncology.org/Anomalies/t1114ID2021.html|title=t(11;14)(q13;q32) IGH/CCND1|website=atlasgeneticsoncology.org|access-date=10 April 2018}}</ref> a [[chromosomal translocation]] in the [[DNA]].

[[Image:Gray602.png|thumb|'''Lymph nodes''' of the head and neck, from Gray's Anatomy (''click image to enlarge'')]]

==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.<ref name="Armitage 2022">{{cite journal |last1=Armitage |first1=James O. |last2=Longo |first2=Dan L. |title=Mantle-Cell Lymphoma |journal=New England Journal of Medicine |date=30 June 2022 |volume=386 |issue=26 |pages=2495–2506 |doi=10.1056/NEJMra2202672|pmid=35767440 }}</ref> 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.<ref name=":3" />

People commonly present with a non-localizing [[lymphadenopathy]] (enlarged lymph nodes) with [[B symptoms]] including fevers, chills and night sweats sometimes being present.<ref name="Armitage 2022" /> 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.<ref name="Armitage 2022" /><ref>{{cite journal|url=http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf|title=Mantle Cell Lymphoma Facts|year=2014|author=Leukemia&Lymphoma Society|website=www.LLS.org|access-date=21 August 2013|archive-date=9 February 2015|archive-url=https://web.archive.org/web/20150209200626/http://www.lls.org/content/nationalcontent/resourcecenter/freeeducationmaterials/lymphoma/pdf/mantlecelllymphoma.pdf|url-status=dead}}</ref> 25% of patients present with a bulky lymphadenopathy characterized by lymph nodes greater than 10&nbsp;cm in size.<ref name="Armitage 2022" /> Other patients may present with [[central nervous system]] (CNS) involvement, which is associated with a very poor prognosis.<ref name="Armitage 2022" /> However, CNS involvement is rare at diagnosis.<ref name=":1">{{Cite journal |last1=McKay |first1=Pamela |last2=Leach |first2=Mike |last3=Jackson |first3=Bob |last4=Robinson |first4=Stephen |last5=Rule |first5=Simon |date=16 May 2018 |title=Guideline for the management of mantle cell lymphoma |journal=British Journal of Haematology |language=en |volume=182 |issue=1 |pages=46–62 |doi=10.1111/bjh.15283 |pmid=29767454 |s2cid=21725055 |issn=0007-1048|doi-access=free |hdl=10026.1/11531 |hdl-access=free }}</ref>

A rare subtype, known as non-nodal mantle cell lymphoma, presents without lymph node swelling (non-nodal) with circulating lymphoma cells (leukemic presentation).<ref name="Chapman-Fredricks 2014">{{cite journal |last1=Chapman-Fredricks |first1=Jennifer |last2=Sandoval-Sus |first2=Jose |last3=Vega |first3=Francisco |last4=Lossos |first4=Izidore S. |title=Progressive leukemic non-nodal mantle cell lymphoma associated with deletions of TP53, ATM, and/or 13q14 |journal=Annals of Diagnostic Pathology |date=1 August 2014 |volume=18 |issue=4 |pages=214–219 |doi=10.1016/j.anndiagpath.2014.03.006|pmid=24852242 }}</ref> 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.<ref name="Orchard 2003">{{cite journal |last1=Orchard |first1=Jenny |last2=Garand |first2=Richard |last3=Davis |first3=Zadie |last4=Babbage |first4=Gavin |last5=Sahota |first5=Surinder |last6=Matutes |first6=Estella |last7=Catovsky |first7=Daniel |last8=Thomas |first8=Peter W. |last9=Avet-Loiseau |first9=Hervé |last10=Oscier |first10=David |title=A subset of t(11;14) lymphoma with mantle cell features displays mutated IgVH genes and includes patients with good prognosis, nonnodal disease |journal=Blood |date=15 June 2003 |volume=101 |issue=12 |pages=4975–4981 |doi=10.1182/blood-2002-06-1864|pmid=12609845 |doi-access=free }}</ref><ref name="Armitage 2022" />

Mantle cell lymphoma has been reported in rare cases to be associated with [[mosquito bite allergy|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.<ref name="pmid27177994">{{cite journal | vauthors = Tatsuno K, Fujiyama T, Matsuoka H, Shimauchi T, Ito T, Tokura Y | title = Clinical categories of exaggerated skin reactions to mosquito bites and their pathophysiology | journal = Journal of Dermatological Science | volume = 82 | issue = 3 | pages = 145–52 | date = June 2016 | pmid = 27177994 | doi = 10.1016/j.jdermsci.2016.04.010 }}</ref><ref name="pmid27900557">{{cite journal | vauthors = Kyriakidis I, Vasileiou E, Karastrati S, Tragiannidis A, Gompakis N, Hatzistilianou M | title = Primary EBV infection and hypersensitivity to mosquito bites: a case report | journal = Virologica Sinica | volume = 31 | issue = 6 | pages = 517–520 | date = December 2016 | pmid = 27900557 | doi = 10.1007/s12250-016-3868-4 | s2cid = 7996104 | pmc = 8193400 }}</ref>

==Pathogenesis==
[[File:Dark, light, mantle and marginal zones of a secondary follicle.png|thumb|Histology of a normal [[lymphoid follicle]], with yellow arrows pointing at mantle zone.]]
MCL, like most [[cancer]]s, results from the acquisition of a combination of (non-inherited) genetic mutations in [[somatic cells]]. This leads to a [[Clonal population|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 <ref>{{Cite web |title=Understanding mantle cell lymphoma |url=https://www.macmillan.org.uk/cancer-information-and-support/lymphoma/non-hodgkin/types/mantle-cell |access-date=2023-10-08 |website=www.macmillan.org.uk |language=en}}</ref> nor inheritable.<ref>{{Cite web |title=Mantle Cell Lymphoma (MCL) |url=https://lymphomation.org/type-MCL.htm |access-date=2023-10-08 |website=lymphomation.org}}</ref>

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 [[Cell nucleus|nuclei]]. Blastic (aka ''blastoid'') variants have intermediate to large-sized cells with finely dispersed [[chromatin]], and are more aggressive in nature.<ref>{{cite web|title=Mantle Cell Lymphoma: An Update for Clinicians|url=http://www.medscape.com/viewarticle/548587_2|work=[[Medscape]]|first=Andre|last=Goy|access-date=18 October 2007}}</ref> 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.<ref>{{Cite web |date=8 Oct 2023 |title=Mantle Cell Lymphoma Facts |url=https://en.wikipedia.org/w/index.php?title=Mantle_cell_lymphoma&action=edit |access-date=8 Oct 2023 |website=Leukemia and Lymphoma Society}}</ref>

==Diagnosis==
[[File:Nodular Mantle Cell Lymphoma - low power view - by Gabriel Caponetti.jpg|thumb|Lymph node with mantle cell lymphoma (low power view, H&E)]]

[[File:Nodular Mantle Cell Lymphoma - high power view - by Gabriel Caponetti.jpg|thumb|Mantle cell lymphoma. Notice the irregular nuclear contours of the medium-sized lymphoma cells and the presence of a pink histiocyte. By immunohistochemistry the lymphoma cells expressed CD20, CD5 and cyclin D1 (high power view, H&E)]]

[[Image:Mantle cell lymphoma - low mag.jpg|thumb|right|150px| [[Micrograph]] of terminal ileum with mantle cell lymphoma (bottom of image). [[H&E stain]].]]
[[Image:Mantle cell lymphoma - low mag - cyclin D1.jpg|thumb|right|150px| [[Micrograph]] of terminal ileum with mantle cell lymphoma (bottom of image - brown colour). [[Cyclin D1]] [[immunostain]].]]
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.<ref name="Armitage 2022" /> 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.<ref name="Armitage 2022" /> In the nodular type, there are large nodules of MCL cells in the lymph node with no germinal centers observed.<ref name="Armitage 2022" /> In MCL with expansion of the mantle zone, the lymphoma cells cause expansion of the mantle zone around normal germinal centers.<ref name="Armitage 2022" /> And in MCL in situ, the lymphoma cells are contained within the mantle zone without expansion.<ref name="Armitage 2022" /> 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.<ref name="Armitage 2022" /> There are cytologic subtypes; the blastoid subtype, is characterized by round nuclei, fine chromatin with some distinct nucleoli.<ref name="Armitage 2022" /> The pleomorphic subtype is characterized by nuclei that vary in size and shape with some having a cleaved form.<ref name="Armitage 2022" /> The blastoid and pleomorphic subtypes of MCL are associated with a more aggressive course.<ref name="Armitage 2022" />

The most common B-cell type seen in MCL is a pre-[[germinal center]] cell (that has not yet undergone the germinal center reaction), that is [[CD5 (protein)|CD5]], [[CD20]], [[CD19]] positive with expression of [[IgM]] and [[IgD]] with [[monoclonal antibody|monoclonal]] kappa and gamma light chains.<ref name="Jain 2022">{{cite journal |last1=Jain |first1=Preetesh |last2=Wang |first2=Michael L. |title=Mantle cell lymphoma in 2022—A comprehensive update on molecular pathogenesis, risk stratification, clinical approach, and current and novel treatments |journal=American Journal of Hematology |date=May 2022 |volume=97 |issue=5 |pages=638–656 |doi=10.1002/ajh.26523|pmid=35266562 |s2cid=247362063 }}</ref> [[CD23]] and [[CD200]] are usually negative and [[cyclin-D1]] (a cell cycle regulatory protein controlling transition from the [[G1 phase]] to the [[S phase]] in the [[cell cycle]]) is classically overexpressed in MCL.<ref name="Jain 2022" /> [[SOX11]] (a transcription factor controlling genes involved in cell survival) is characteristically over-expressed in MCL as well.<ref name="Jain 2022" /> [[Ki-67 (protein)|Ki-67]], a marker of cell proliferation, if elevated (greater than 30% expression) is associated with an aggressive course of MCL.<ref name="Jain 2022" />

Chromosomal assessment using [[fluorescence in situ hybridization]] shows the characteristic chromosomal translocation t(11;14)(q13;q32) which is present in 90–95% of cases of MCL.<ref name="Jain 2022" /> Imaging using [[computed tomography]] (CT) or [[positron emission tomography–computed tomography]] is required to assess for any extra-nodal or distal involvement.<ref name="Jain 2022" />

[[MRI]] of the brain and the spine are performed in cases of MCL with suspected central nervous system involvement.<ref name="Jain 2022" /> And, since 40-80% of MCL presents with gastrointestinal involvement at the time of diagnosis, [[endoscopy]] ([[colonoscopy]] and [[esophagogastroduodenoscopy]] (EGD)) with biopsies may also aid in the diagnosis, but they are not always required for the diagnosis of MCL.<ref name="Jain 2022" />

The diagnosis may be complicated as a minority of cases of [[multiple myeloma]], [[chronic lymphocytic leukemia]] and [[plasma cell leukemia]] may also present with the t(11;14)(q13;q32) translocation.<ref name="Jain 2022" /> 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.<ref name="Jain 2022" /> The cyclin-D1-negative MCL subtypes usually result in lymphomagenesis via over-expression of [[cyclin D2]], [[cyclin D3]] or [[cyclin E]], which also lead to cell cycle hyperactivity and have a similar prognosis to the main cyclin-D1 variant of MCL.<ref name="Armitage 2022" />

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]].<ref name="Jain 2022" />

==Treatments==
There are no proven standards of treatment for MCL, and there is no consensus among specialists on how to treat it optimally.<ref>{{cite journal | pmc=4298490 | pmid=25642314 | doi=10.1177/2040620714561579 | volume=6 |issue = 1| title=Mantle cell lymphoma: observation to transplantation | year=2015 | journal=Ther Adv Hematol | pages=37–48 | vauthors=Rajabi B, Sweetenham JW}}</ref> 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.<ref name=":3" /> 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.<ref>{{Cite journal |last1=McCulloch |first1=Rory |last2=Smith |first2=Alexandra |last3=Crosbie |first3=Nicola |last4=Patmore |first4=Russell |last5=Rule |first5=Simon |date=26 November 2018 |title=Receiving treatment at a specialist centre confers an overall survival benefit for patients with mantle cell lymphoma |journal=British Journal of Haematology |language=en |volume=185 |issue=5 |pages=1002–1004 |doi=10.1111/bjh.15696 |pmid=30474177 |s2cid=53731469 |issn=0007-1048|doi-access=free }}</ref> 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.<ref name=":1" />

There are four classes of treatments in general use: [[chemotherapy]], [[immunotherapy]], [[radioimmunotherapy]] 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.<ref>{{Cite web |title=Therapeutic options for relapsed/refractory mantle cell lymphoma |url=https://ashpublications.org/blood/article/139/5/666/477438/Therapeutic-options-for-relapsed-refractory-mantle |access-date=2023-10-08 |website=ashpublications.org}}</ref>

===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 (chemotherapy)|CHOP]] with [[rituximab]] 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]] with rituximab.<ref>{{Cite web |url=http://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf |title=Archived copy |access-date=18 March 2015 |archive-url=https://web.archive.org/web/20170623015817/https://www.nccn.org/professionals/physician_gls/pdf/nhl.pdf |archive-date=23 June 2017 |url-status=dead }}</ref>

Second line treatment may include [[fludarabine]], combined with [[cyclophosphamide]] and/or [[mitoxantrone]], usually with rituximab. [[Cladribine]] and [[clofarabine]] 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]], [[etoposide]], [[procarbazine]], and cyclophosphamide, taken orally, has proven effective for relapsed patients. According to Dr. John Leonard, PEP-C may have anti-angiogenetic properties,<ref>{{Cite web |url=http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=23&abstractID=104642 |title=Oral combination chemotherapy with Pep-C (C3) for mantle cell lymphoma (MCL): Daily prednisone, etoposide, procarbazine and cyclophosphamide – ASCO |access-date=15 January 2008 |archive-date=29 September 2008 |archive-url=https://web.archive.org/web/20080929020107/http://www.asco.org/ASCO/Abstracts+%26+Virtual+Meeting/Abstracts?&vmview=abst_detail_view&confID=23&abstractID=104642 |url-status=dead }}{{full citation needed|date=July 2016}}</ref><ref>{{cite web |url=http://www.mantlecelllymphoma.org/default.asp?pgid=122 |title=Dr. John Leonard |access-date=24 February 2008 |url-status=dead |archive-url=https://web.archive.org/web/20080417044134/http://www.mantlecelllymphoma.org/default.asp?pgid=122 |archive-date=17 April 2008 }}{{full citation needed|date=July 2016}}</ref> something that he and his colleagues are testing through an ongoing drug trial.<ref>{{Cite web|url=http://clinicaltrials.gov/ct2/show/NCT00151281?cond=%22Lymphoma%2C+Mantle-Cell%22&rank=55|title = Phase II Trial of Anti-Angiogenic Therapy with RT-PEPC in Patients with Relapsed Mantle Cell Lymphoma|date = 26 June 2018}}</ref>

Another approach involves using very high doses of chemotherapy, sometimes combined with [[total body irradiation]] (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]]), using either [[autologous stem cell transplantation]], or those from a matched donor (an [[Allotransplantation|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<ref>{{cite web |url=http://www.nordic-lymphoma.org/mcl2eng.htm |title=Background |access-date=15 February 2008 |url-status=dead |archive-url=https://web.archive.org/web/20080416134741/http://www.nordic-lymphoma.org/mcl2eng.htm |archive-date=16 April 2008 }}</ref> 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.<ref>{{Cite web | url=http://www.docguide.com/news/content.nsf/news/852571020057CCF6852573AD006260EB?OpenDocument&id=48DDE4A73E09A969852568880078C249&c=Lymphomas&count=10 |title = Mantle Cell Lymphoma is Curable with Intensive Immunochemotherapy |work=DocGuide}}</ref><ref>{{cite web | url=http://www.abstracts2view.com/hem07/view.php?nu=HEM07L1_6026&terms= | archive-url=https://web.archive.org/web/20080417174258/http://www.abstracts2view.com/hem07/view.php?nu=HEM07L1_6026&terms= | archive-date=17 April 2008 | title=Result Content View }}</ref>

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.<ref>{{cite journal |vauthors=Ye H, Desai A, Huang S, Jung D, Champlin R, Zeng D, Yan F, Nomie K, Romaguera J, Ahmed M, Wang ML | display-authors=3 |title=Paramount therapy for young and fit patients with mantle cell lymphoma: strategies for front-line therapy |journal=J. Exp. Clin. Cancer Res. |volume=37 |issue=1 |pages=150 |date=July 2018 |pmid=30005678 |pmc=6044039 |doi=10.1186/s13046-018-0800-9 | doi-access=free }}</ref><ref>{{cite journal |vauthors=Ye H, Desai A, Zeng D, Romaguera J, Wang ML | display-authors=3 |title=Frontline Treatment for Older Patients with Mantle Cell Lymphoma |journal=Oncologist |volume=23 |issue=11 |pages=1337–1348 |date=November 2018 |pmid=29895632 |pmc=6291324 |doi=10.1634/theoncologist.2017-0470 }}</ref>

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.<ref>{{cite journal |vauthors=Rummel MJ, Niederle N, Maschmeyer G, Banat GA, von Grünhagen U, Losem C, Kofahl-Krause D, Heil G, Welslau M, Balser C, Kaiser U, Weidmann E, Dürk H, Ballo H, Stauch M, Roller F, Barth J, Hoelzer D, Hinke A, Brugger W | display-authors=3 |title=Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial |journal=Lancet |volume=381 |issue=9873 |pages=1203–10 |date=April 2013 |pmid=23433739 |doi=10.1016/S0140-6736(12)61763-2| s2cid=27886488 }}</ref>

===Immunotherapy===
[[Immunotherapy|Immune-based therapy]] is dominated by the use of the [[rituximab]] 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{{when|date=November 2019}} 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.<ref>{{cite journal |vauthors=Kaufmann H, Raderer M, Wöhrer S, Püspök A, Bankier A, Zielinski C, Chott A, Drach J | display-authors=3 |title=Antitumor activity of rituximab plus thalidomide in patients with relapsed/refractory mantle cell lymphoma |journal=Blood |volume=104 |issue=8 |pages=2269–71 |date=October 2004 |pmid=15166030 |doi=10.1182/blood-2004-03-1091| s2cid=24548471 |doi-access=free }}</ref>  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]]s, [[adoptive cell transfer]], and [[immunotransplant]], which combines vaccination and [[Hematopoietic stem cell transplantation|autologous stem cell transplant]].  As of 2023,  active immunotherapies are not currently a standard of care,<ref name=":3" /> but numerous [[clinical trial]]s are ongoing.<ref>{{cite web|url=http://clinicaltrials.gov/ct2/show/NCT00101101|title=Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00101101|access-date=28 February 2016|website=ClinicalTrials.gov}}</ref><ref>{{cite web|url=http://clinicaltrials.gov/ct2/show/NCT00020215|title=Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00005780|access-date=28 February 2016|website=ClinicalTrials.gov}}</ref><ref>{{cite web|url=http://clinicaltrials.gov/ct2/show/NCT00490529|title=Chemotherapy Plus Vaccination to Treat Mantle Cell Lymphoma – NCT00490529|access-date=28 February 2016|website=ClinicalTrials.gov}}</ref>

===Targeted therapy===
Two Bruton tyrosine kinase inhibitors (BTKi), one In November 2013, [[ibrutinib]] (brand name [[Imbruvica]], Pharmacyclics LLC) and one in October 2017, [[acalabrutinib]] (brand name Calquence, AstraZeneca Pharmaceuticals LP) were approved in the United States for treating mantle cell lymphoma.<ref>{{cite press release | title=FDA approves Imbruvica for rare blood cancers | website=U.S. [[Food and Drug Administration]] (FDA)| date=13 November 2013 }} {{cite press release | title=FDA approves Calquence, on October 31, 2017, the Food and Drug Administration granted accelerated approval to acalabrutinib, (AstraZeneca Pharmaceuticals Inc. under license of Acerta Pharma BV) with an indication for the treatment of adults with mantle cell lymphoma (MCL) who have received at least one prior round of therapy. | url=https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | archive-url=https://web.archive.org/web/20170216021732/https://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm374761.htm | archive-date=16 February 2017 | url-status=dead | access-date=15 November 2019 }}</ref> However, although these medications are beneficial their duration is short and patients typically relapse.<ref name=":3" />

In November 2019, [[zanubrutinib]] (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.<ref name="FDA Zanubrutinib PR">{{cite press release | title=FDA approves therapy to treat patients with relapsed and refractory mantle cell lymphoma supported by clinical trial results showing high response rate of tumor shrinkage | website=U.S. [[Food and Drug Administration]] (FDA) | date=14 November 2019 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-therapy-treat-patients-relapsed-and-refractory-mantle-cell-lymphoma-supported-clinical | archive-url=https://web.archive.org/web/20191115031304/https://www.fda.gov/news-events/press-announcements/fda-approves-therapy-treat-patients-relapsed-and-refractory-mantle-cell-lymphoma-supported-clinical | url-status=dead | archive-date=15 November 2019 | access-date=15 November 2019}} {{PD-notice}}</ref>

[[Pirtobrutinib]] (Jaypirca) was approved for medical use in the United States in January 2023.<ref>{{cite press release | title=U.S. FDA Approves Jaypirca (pirtobrutinib), the First and Only Non-Covalent (Reversible) BTK Inhibitor, for Adult Patients with Relapsed or Refractory Mantle Cell Lymphoma After at Least Two Lines of Systemic Therapy, Including a BTK Inhibitor | publisher=Eli Lilly | via=PR Newswire | date=27 January 2023 | url=https://www.prnewswire.com/news-releases/us-fda-approves-jaypirca-pirtobrutinib-the-first-and-only-non-covalent-reversible-btk-inhibitor-for-adult-patients-with-relapsed-or-refractory-mantle-cell-lymphoma-after-at-least-two-lines-of-systemic-therapy-including-a-301732669.html | access-date=31 January 2023}}</ref>

=== 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.<ref name="FDA Tecartus PR">{{cite web | title=FDA Approves First Cell-Based Gene Therapy For Adult Patients with Relapsed or Refractory MCL | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 July 2020 | url=https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl | archive-url=https://web.archive.org/web/20200725050713/https://www.fda.gov/news-events/press-announcements/fda-approves-first-cell-based-gene-therapy-adult-patients-relapsed-or-refractory-mcl | url-status=dead | archive-date=25 July 2020 | access-date=24 July 2020}} {{PD-notice}}</ref><ref name="FDA Tecartus">{{cite web | title=Tecartus | website=U.S. [[Food and Drug Administration]] (FDA) | date=24 July 2020 | url=https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel | archive-url=https://web.archive.org/web/20200725050728/https://www.fda.gov/vaccines-blood-biologics/cellular-gene-therapy-products/tecartus-brexucabtagene-autoleucel | url-status=dead | archive-date=25 July 2020 | access-date=24 July 2020 | id=STN: BL 125703 }}</ref><ref name="Kite PR">{{cite press release | title=U.S. FDA Approves Kite's Tecartus, the First and Only CAR T Treatment for Relapsed or Refractory Mantle Cell Lymphoma | publisher=Kite Pharma | via=Business Wire | date=24 July 2020 | url=https://www.businesswire.com/news/home/20200724005428/en/ | access-date=24 July 2020}}</ref> It was approved for medical use in the European Union in December 2020.<ref name="Tecartus EPAR">{{cite web | title=Tecartus EPAR | website=[[European Medicines Agency]] (EMA) | date=13 October 2020 | url=https://www.ema.europa.eu/en/medicines/human/EPAR/tecartus | access-date=25 January 2021}}</ref>

Each dose of brexucabtagene autoleucel is a customized treatment created using the recipient's own immune system to help fight the lymphoma.<ref name="FDA Tecartus PR" /> The recipient's [[T 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.<ref name="FDA Tecartus PR" /> These modified T cells are then infused back into the recipient.<ref name="FDA Tecartus PR" />

==Prognosis==
Recent{{when|date=August 2020}} 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,{{when|date=August 2020}} 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{{when|date=August 2020}} 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).<ref>British Journal of Haematology 20 November 2018</ref>

The overall [[5-year survival rate]] for MCL is generally 50%<ref>Most recent values in:{{cite journal |vauthors=Herrmann A, Hoster E, Zwingers T, Brittinger G, Engelhard M, Meusers P, Reiser M, Forstpointner R, Metzner B, Peter N, Wörmann B, Trümper L, Pfreundschuh M, Einsele H, Hiddemann W, Unterhalt M, Dreyling M | display-authors=3 |title=Improvement of overall survival in advanced stage mantle cell lymphoma |journal=J. Clin. Oncol. |volume=27 |issue=4 |pages=511–8 |date=February 2009 |pmid=19075279 |doi=10.1200/JCO.2008.16.8435|doi-access=free }}</ref> (advanced stage MCL) to 70%<ref>{{cite journal |vauthors=Leitch HA, Gascoyne RD, Chhanabhai M, Voss NJ, Klasa R, Connors JM |title=Limited-stage mantle-cell lymphoma |journal=Ann. Oncol. |volume=14 |issue=10 |pages=1555–61 |date=October 2003 |pmid=14504058 |doi=10.1093/annonc/mdg414|doi-access=free }}</ref> (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.<ref name=":1" /> 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.<ref name=":0">{{Cite journal |last1=Wang |first1=Yu |last2=Ma |first2=Shuangge |date=22 Feb 2014 |title=Risk Factors for Etiology and Prognosis of Mantle Cell Lymphoma |journal=Expert Review of Hematology |volume=7 |issue=2 |pages=233–243 |doi=10.1586/17474086.2014.889561 |issn=1747-4086 |pmc=4465399 |pmid=24559208}}</ref>

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.<ref>{{cite journal |vauthors=Hoster E, Dreyling M, Klapper W, Gisselbrecht C, van Hoof A, Kluin-Nelemans HC, Pfreundschuh M, Reiser M, Metzner B, Einsele H, Peter N, Jung W, Wörmann B, Ludwig WD, Dührsen U, Eimermacher H, Wandt H, Hasford J, Hiddemann W, Unterhalt M | display-authors=3 |title=A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma |journal=Blood |volume=111 |issue=2 |pages=558–65 |date=January 2008 |pmid=17962512 |doi=10.1182/blood-2007-06-095331| s2cid=19785998 |doi-access=free }}</ref>

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.{{medical citation needed|date=August 2013}}

There are a number of prognostic indicators that have been studied. There is not universal agreement on their importance or usefulness in prognosis.<ref name=":0" />

[[Ki-67 (Biology)|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.<ref>{{Cite journal |last=Katzenberger |first=Tiemo |date=15 April 2006 |title=The Ki67 proliferation index is a quantitative indicator of clinical risk in mantle cell lymphoma |url=https://ashpublications.org/blood/article/107/8/3407/22238/The-Ki67-proliferation-index-is-a-quantitative |access-date=2023-10-09 |journal=Blood|volume=107 |issue=8 |page=3407 |doi=10.1182/blood-2005-10-4079 |pmid=16597597 |doi-access=free }}</ref>

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.<ref name=":2">{{Cite journal |last1=Dreyling |first1=Martin |last2=Klapper |first2=Wolfram |last3=Rule |first3=Simon |title=Blastoid and pleomorphic mantle cell lymphoma: still a diagnostic and therapeutic challenge! |url=https://ashpublications.org/blood/article/132/26/2722/39681/Blastoid-and-pleomorphic-mantle-cell-lymphoma |access-date=2023-10-09 |journal=Blood|date=2018 |volume=132 |issue=26 |pages=2722–2729 |doi=10.1182/blood-2017-08-737502 |pmid=30385481 |s2cid=54433020 |doi-access=free }}</ref> Although survival of most blastic patients is shorter, some data shows that 25% of blastic MCL patients survive to 5 years.<ref name=":2" /> That is longer than diffuse type and almost as long as nodular (almost 7 yrs).{{medical citation needed|date=August 2013}}

[[Beta-2 microglobulin]] 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{{when|date=November 2019}} fully validated.{{medical citation needed|date=August 2013}}

Testing for high levels of [[lactate dehydrogenase]] 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 <ref>{{Citation |last1=Farhana |first1=Aisha |title=Biochemistry, Lactate Dehydrogenase |date=2023 |url=http://www.ncbi.nlm.nih.gov/books/NBK557536/ |work=StatPearls |access-date=2023-10-09 |place=Treasure Island (FL) |publisher=StatPearls Publishing |pmid=32491468 |last2=Lappin |first2=Sarah L.}}</ref> but the clinical interpretation will depend upon the patient's symptoms.

==Epidemiology==
6% of [[non-Hodgkin's lymphoma]] cases are mantle cell lymphoma.<ref name="Skarbnik2015"/> {{As of|2015}}, the ratio of males to females affected is about 4:1.<ref name="Skarbnik2015"/>

==See also==
* [[In situ lymphoid neoplasia|''In situ'' mantle cell lymphoma]]
* [[List of hematologic conditions]]

==References==
{{reflist}}

==Further reading==
* {{cite journal |vauthors=Cohen JB, Zain JM, Kahl BS |title=Current Approaches to Mantle Cell Lymphoma: Diagnosis, Prognosis, and Therapies |journal=Am Soc Clin Oncol Educ Book |volume=37 |issue= 37|pages=512–25 |date=2017 |pmid=28561694 |doi=10.1200/EDBK_175448 }}
* {{cite journal |vauthors=Dreyling M, Ferrero S, Hermine O |title=How to manage mantle cell lymphoma |journal=Leukemia |volume=28 |issue=11 |pages=2117–30 |date=November 2014 |pmid=24854989 |doi=10.1038/leu.2014.171 |s2cid=22105743 }}
* {{cite journal |vauthors=Schieber M, Gordon LI, Karmali R |title=Current overview and treatment of mantle cell lymphoma |journal=F1000Res |volume=7 |pages= 1136|date=2018 |pmid=30109020 |pmc=6069726 |doi=10.12688/f1000research.14122.1 |doi-access=free }}

==External links==
{{Medical resources
|  DiseasesDB     = 
|  ICD10          = {{ICD10|C|83|1|c|83}}
|  ICD9           = {{ICD9|200.4}}
|  ICDO           = {{ICDO|9673|3}}
|  OMIM           = 
|  MedlinePlus    = 
|  eMedicineSubj  = med
|  eMedicineTopic = 1361
|  MeshID         = D020522
}}

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[[Category:Non-Hodgkin lymphoma]]