Guidelines for the investigation and management of mantle cell lymphoma

Abstract

The guideline group was selected to be representative of UK-based medical experts and patients representatives. Ovid MEDLINE, EMBASE and NCBI Pubmed were searched systematically for publications in English from 1980 to 2011 using the MeSH subheading ‘lymphoma, mantle cell’ and ‘lymphoma, mantle cell’ as a keyword, as well as all subheadings. In addition, all references to mantle cell lymphoma in the World Health Organization Classification of Tumours of Haematopoietic and Lymphoid Tissue (Swerdlow et al, 2008) and the British Committee for Standards in Haematology (BCSH) Guideline: Best Practice in Lymphoma Diagnosis and Reporting (Parker et al, 2010) have been included. The writing group produced the draft guideline, which was subsequently revised by consensus by members of the Haemato-oncology Task Force of the BCSH. The guideline was then reviewed by a sounding board of approximately 50 UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The ‘GRADE’ system was used to quote levels and grades of evidence, details of which can be found in Appendix I. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of patients with mantle cell lymphoma. The guidance may not be appropriate to patients with other lymphoma sub-types and in all cases individual patient circumstances may dictate an alternative approach. This guideline is the first BCSH guideline on the topic of mantle cell lymphoma, and therefore, does not supersede any previous guidance. The section on diagnosis of mantle cell lymphoma, should be considered supplementary to the BCSH Guideline: Best Practice in Lymphoma Diagnosis and Reporting (Parker et al, 2010). The guideline is in date at time of publication. Any updates will be posted on the BCSH website (http://www.bcshguidelines.com/). Mantle cell lymphoma (MCL) is a B-cell malignancy with unique biological, pathological and clinical features, which comprises approximately 3–10% of all non-Hodgkin lymphomas (NHLs) (Swerdlow et al, 2008). It is characterized by the chromosomal translocation t(11;14)(q13;q32), which results in overexpression of the cell cycle protein cyclin D1 (Akiyama et al, 1994; Campo et al, 1999). MCL arises in older adults (median age of presentation 60–65 years) and has a male predominance (Argatoff et al, 1997; Bosch et al, 1998). The challenge of MCL is that it has the worst features of both high and low grade NHL; an aggressive clinical course, but with a pattern of resistant and relapsing disease rendering it incurable to standard therapy. Median survival is 4–5 years (Herrmann et al, 2009). There is evidence to suggest that this has increased over recent years from the previous median survival of 2–3 years, as a result of improved combination chemotherapies (discussed below) and supportive care. However, no standard of care is recognized, and this disease remains very difficult to manage. A number of studies have described the clinical presentation of MCL (Zucca et al, 1995; Argatoff et al, 1997; Bosch et al, 1998; Tiemann et al, 2005). The majority (> 90%) of patients present with advanced stage (Ann Arbor III-IV) disease. Lymphadenopathy is generally widespread at diagnosis, and splenomegaly, bone marrow infiltration and leukaemic involvement are common. Bulk disease at diagnosis and B-symptoms are less common. Extranodal involvement is frequent, particularly affecting the gastro-intestinal (GI) tract (Romaguera et al, 2003) and liver, but involvement of breast, lung, skin, soft tissue, salivary gland and orbit are also seen. Involvement of more than two extranodal sites is seen in 30–50% of patients (Jares & Campo, 2008). Spread to the central nervous system (CNS) can occur, but is rare at diagnosis, tending to occur as a late event in the course of the disease, where it is associated with widespread relapse and short survival (Ferrer et al, 2008). The clinical course is heterogeneous. Clinical presentation can correlate with pathological sub-type (discussed below); patients with the blastoid variant tend to have a very aggressive clinical course, may be refractory to treatment and have short survival. In contrast, it is recognized that a proportion of cases (10–30%) may present with more indolent disease (Eve et al, 2009a; Martin et al, 2009). These patients usually present with splenomegaly and a peripheral blood lymphocytosis, and lack significant nodal disease (Nodit et al, et al, is in the of the of the disease, and the in which it an clinical are to provide a for treatment of patients with The diagnosis of MCL should be by an of an extranodal by bone marrow in the majority of may be to is A diagnosis may also be on a peripheral blood in cases with a leukaemic In the which for of the of the is usually and is by a less a of a of to with (Swerdlow et al, Argatoff et al, 1997; Tiemann et al, 2005). A mantle pattern is seen in a of cases et al, 2005). is and may also be in cases with a A cell variant lymphoma, is the blastoid lymphoma and the which may be on with B-cell lymphoma (Swerdlow et al, et al, 1995; Argatoff et al, 1997; et al, 1997; Tiemann et al, 2005). The features are in of extranodal as and salivary In the is and and less is (Argatoff et al, 1997; et al, 1998). should & and in to may be on by on by In to a D1 should be in all of B-cell lymphoma The majority of MCL cases and cyclin The is usually for and et al, 1995; et al, 1995; Argatoff et al, 1997; a of this may be in of in may be difficult in of the of of A with the pattern for is in MCL with an is well is seen in approximately of cases et al, et al, et al, et al, 2010). of and is recognized in a of cases and may to an diagnosis et al, et al, et al, et al, 2010). of cyclin D1 is seen in the majority of cases and lack of should the diagnosis of MCL et al, 1995; et al, to cyclin D1 are and lack of is usually to lack of et al, 2005). In cases with in may be for the translocation on both and peripheral blood to the diagnosis et al, et al, is in MCL et al, et al, 2009). It is that may have a in the of MCL in the and generally on peripheral blood bone marrow can be in of a diagnosis of MCL with and of is seen in a proportion of particularly in with blastoid et al, 2008). is not for of cyclin in patients with a leukaemic cyclin D1 may be on of peripheral blood two should not be is with The of MCL is the in overexpression of cyclin D1 by the at to cell cycle at the et al, et al, The translocation may be by et al, et al, et al, The has the that it can be on and can be to and In the of the translocation should be in cases with an cyclin D1 clinical of may be by of by by for are in MCL and the of is associated with patient survival et al, et al, et al, et al, 2008). MCL is associated with a is in the features have been as blastoid and with of et al, 1995; Argatoff et al, 1997; et al, 1997; et al, of blastoid may be difficult in of in and the of cell is the in et al, et al, et al, 2008). in of the is well guidance has been produced by the MCL which that the lymphoma in of two representative improved in this et al, 2009). in the a proportion of patients present with indolent disease. of this variant at presentation is suggest that lack of of is associated with indolent disease et al, 2010). The leukaemic in indolent MCL have been found to be in to the usually seen in is also in this group by et al, of is to as a for of to MCL can occur as a result of of for cyclin D1 in the standard lymphoma is and may to and to as may the D1 is by cell and may be in to of which may to in bone marrow a the bone marrow and should A proportion of cases cyclin D1 et al, 2008). for cyclin which may in of where the of the malignancy is by an cyclin cases of MCL the translocation have been recognized et al, et al, et al, 2009). The than cyclin D1 and clinical course are to cases of The lymphoma is characterized by overexpression of cyclin cyclin and has a variant These lymphomas have an to MCL and are as a variant of this and should be as The of has been as a of this et al, 2009). results have been with this and as a is not It is for the to be of this and to the diagnosis with a B-cell lymphoma with features of to a for investigation should be in a patient with MCL to provide to are to the stage of disease, and for therapy. of at using a standard as the World Health et al, is of the and should be with and where appropriate. may be for of disease, with where clinical is high (Ferrer et al, & et al, 2009). is used in the of of lymphoma, remains to be in It has been that MCL is particularly the blastoid variant and nodal disease et al, 2008). However, in to other high grade has been to have in particularly extranodal disease et al, 2010) and of in the of the of a clinical be peripheral blood should a blood and peripheral blood A peripheral blood is seen in of patients with and by is should and and marrow should an for by and a for and of by with should be is any clinical of disease, and can be considered in blastoid variant disease. and as of in MCL et al, on the that studies have involvement by MCL of the tract in of cases et al, However, it has been that this of clinical (Romaguera et al, 2003) and be for all patients at should be on the of clinical where are any significant clinical stage disease is present and with is is of any and also should be for cyclin D1 where is it is that patients for and and in patients with no other should be where should be using and the patient with the disease for is to of but is not MCL is in of it is that a be is in this as a disease with generally it has clear that MCL more than and for this have been to features that may has been features may be of The system used to MCL is the as the Arbor used in lymphoma and other of patients with MCL have blood and bone marrow involvement at clinical stage used in is not The does not well used in of patients with and is not in this et al, et al, A system for the MCL has been on using features of the in patients with advanced stage MCL et al, This patients low and high with of the survival of to this the MCL an at However, that the system more and the also a at of and blood cell This also patients the of and and was as as the to the and the have been in et al, et al, 2010). It is by the of the that of will be it can be used for the of in individual patients et al, et al, & 2009). In of as a it can provide to the at as described is of the an alternative is to to provide a more et al, The and in et al, 2010). that more of are the may be a at There is a lack of to treatment of it is a and it was recognized as a in the revised of in et al, In addition, MCL patients have been with other in clinical it is where patients with MCL should be the of a clinical of to UK clinical for patients with MCL can be found in Appendix The guidance and for patients not in a clinical is to studies more than MCL very studies in are considered of in the et al, et al, et al, et al, as other are not to the are in the A very proportion of patients will present with evidence for management of this group is However, in this may be appropriate and can result in MCL is and has been used as for disease with & in patients with stage and MCL et al, was to of the in combination with in of In of the an of in this survival of with for not In addition, a from the British Lymphoma et al, cases with therapy. patients stage disease, and were with of patients a were of the patients at and patients in at and that MCL may be with in a proportion of disease is should be with bone marrow and as described the of a clinical with be a approach. MCL is recognized as the worst of all of lymphoma. patients well to is short and survival is has been in the a of patients has disease that in a more indolent are it is to a and A of patients that for of patients were by and treatment was for a median of with et al, 2009). It is of that patients in this were and generally treatment than The majority of patients the is to the the of will on the of therapy. Clinical of treatment in MCL are in should be patients to peripheral blood cell and less patients for this is not an patients where the is to to high and in first should be with the of as a as However, the majority of patients are where a is not a of is in combination with and are It is that for this is no and it is difficult to any MCL was with lymphomas in clinical studies and with et al, et al, 1995; et al, et al, and and et al, et al, et al, of the studies but the pattern was of but short and of at combination in of In of an in the et al, not a survival This has been in The Lymphoma of patients were with no survival of be et al, the an of in patients and in et al, 1998). In not for the more is no evidence that any However, the lack of evidence, remains a used combination in this disease and the in this have it as a treatment The of in MCL has been in the with used as a of are seen et al, 2005). However, used in combination with as to approximately et al, et al, The of the not be in to the recognized may with this is & et al, A of the MCL patients and et al, were in the of was in the with particularly high the that the of that should be to MCL and should be any to a in and are not as of treatment where is has in the evidence that it be used in combination with for to be seen et al, et al, has in MCL et al, et al, a to may have an to in particularly where less aggressive is The combination of and an of et al, 2005). A of was with the and this et al, patients with of indolent lymphoma. has less in MCL than in other B-cell lymphomas lymphoma and However, it has been that the of to the et al, et al, et al, A and of et al, that with may be to with to in MCL for was a number of were this The results of a recent with et al, has evidence of the of in MCL with in and with in MCL and et al, and and et al, 2005). of are in it is that the median age of patients in studies was and years, that may be in an older patient has been in that has in MCL et al, et al, et al, are in and is not but may be an in patients in is to of but not et al, et al, The MCL MCL the of in to et al, and is will be of from this in suggest that may and particularly with as et al, is not as as more for to et al, et al, et al, 2005). There is an of the of in MCL with and this is incorporated first studies have an of and of was first in this as of the with results in et al, 1998). The of to this high of et al, et al, which in of the that this does not The of this remains marrow and and which a of A recent et al, the is an for in it with significant In a (median age to and were high were not and of patients with of patients were to the of treatment to The results with this not to be in the The of from were subsequently incorporated other combination The results of the et al, 2008) were to the with the the two the of and in The MCL of and by a for to and to the the group with and This a time to treatment not an in et al, 2010). The and of as to an with and then to on patients have been to date et al, 2010). This was well with of patients the as and the the of were with and of results are and not provide any survival the are to seen with standard and the of These are generally for the older patient years) to increased (Romaguera et al, 2005). the and than the of remains with a pattern of In of is an to the in patients with and peripheral blood cell This has been to survival and for the treatment of advanced stage disease are in The treatment in years) less patients years are not for and should of has been it is recognized that no and The and combination of will be by patient and and should be in the treatment of and patients years with no significant evidence that treatment is with a to a to and in MCL is using the of in MCL is not and this of should not be used to the of a clinical et al, disease for the has been to have particularly et al, it be at present of a patients where is a first relapse in MCL the median survival is approximately the patient has not peripheral blood cell as of but is considered for at of of a with an is a clinical (discussed There is no standard generally and the of the are than therapy. The of in and is generally of the of There are publications at in lymphoma that patients with These are studies and usually than as have not been In for all of the studies the are and it is to on It is that is standard for and will the treatment appropriate for the individual The of will be by patient bone marrow and of In patients have an should be as to the patient is for the should be to a and then A should be used in first therapy. and are less in the than as therapy. In the studies of this patients with disease were with a and at patients as a of et al, 1998). the patient is not for has no then a number of treatment in this It is that where the patient has previous of a be at that where are not used in then should be considered at first can be and with and et al, and the patient has more than previous of are a number of with These are in of are in in combination with where is as a in the in approximately of patients et al, 1998; et al, with a median of to be There is the of in combination with in the et al, This the of and with There were patients with MCL in this was no significant in was a significant survival the of not In a to the a MCL patients were with were and no et al, The median was the a proportion of patients in the years has been by the in the of for in disease. the of in of to in MCL with to in disease et al, et al, et al, et al, This on to a et al, using at a and patients were and a of of The median time to with was and can be very in patients a In the of the et al, the median of was but for patients a this has to be with a number of of in combination with are a of clinical and with and are The combination of with in patients produced an of but a of et al, The of is also with evidence that a a of in combination with may be as but less et al, 2010). a has been by the for in at a of for in MCL produced an of and median of of et al, 2005). A used a for to a of et al, 2008). The was with patient a and a median of of These results are was less with the grade The a two of for and then et al, A of with disease patients were with the of a than the and a objective The a The median for the group and the were and with on of the In of as the in for the treatment of it is in this guideline as a treatment There are a number of that have in this disease has in MCL et al, 1999). In with were with a short of et al, 1998). with other this is by the of other The of with increased to with et al, In a of patients at first relapse was used with in a et al, 2005). The was with and of The of to as described et al, to an of and the of improved the of the with as a in the to of with and a median of et al, 2008). has in In a of patients with disease it was in combination with and et al, The were at and but the was very short at is used in In the are two with an with and a of et al, 2005). was to this a and but the number of patients was to et al, 2008). is an that in a of have patients with The patients with an of with a and a of of et al, 2009). A MCL with an of of et al, The with this is with over patients in the by et a is in as a is less than in a of was in combination with the was with a et al, These were with a of studies are the of to and have been to the low In a of patients the was a The median of was et al, 2008). The of and not to patients were on this with an of with and a median of et al, 2010). other have been in MCL with as a to a in patients with a median of of et al, a protein produced no objective in a of a number of patients from et al, 2008). cell by cell have been to be in as has been of the in the of in this incurable disease. It is to that age the of this treatment in the majority of patients with first in the et al, to date has been the of in of MCL et al, 2005). In this patients to were to a cycle of and by and The median was in the group with the group There was no significant in with in the The was seen in a with and years, the in at in the and in the group studies have been have the of et al, et al, et a years median survival and a of and was used to first in have relapse and of and patients with first but disease and disease at first relapse et al, 2005). In an for and of with a median of years, the and was and at was the in with in first from et al, In a of patients it was that was of to years but the of patients with MCL was et al, 2010). as is that patients an as as of the therapy. the patient has not as of but is considered for at may be considered et al, the evidence that in disease is of is with no to A of in of been no in by number of previous et al, that may be seen There is no evidence to suggest that is in this with no seen in survival from to the results of have in with and of in the et used at the time of cell to the cell by was and at years, which with used as of the an disease to et al, In with does not et al, and does not to a of the of in in MCL is There is evidence that of in the of may clinical relapse et al, et al, 2009). The of the and was by et patients with disease were with and at The a of at years with no et al, the of this in patients with disease. and associated with the of and clinical in the The of has been of is associated with a of the median and median et al, may patients at of relapse may be for therapy. relapse have for disease In this clinical studies have disease with the high has the of this et al, 1998; et al, et al, et al, et al, 2005). with other disease have to to the the of in MCL a more in patients relapsing with disease et al, of a by the Lymphoma of the et al, were very with and of and studies have more A of using a et al, patients with MCL patients with a median of no patient in and patient with disease at has at years was and was as The of and at years were and of in patients with MCL was with other lymphomas In a of in the the British Society of and a relapse of at years, with a and of and et al, 2010). The evidence of a was by the increased relapse associated with and the of relapsing patients with The results to date using in MCL to the in of in patient and the evidence for the of an and as has a in the management of disease. evidence for a for in refractory disease et al, 2010). The in first remains is considered a Clinical the the and in is to be and at the time of to the the British Society for Haematology the any for the of & in of to the of and to the and writing of this is by the & have and for board from has from and & has from has and for board from has for board from & and of the other have a of Task at time of writing this guideline was and and and BCSH have used the for levels of evidence and in guidance is to clinical is the of a to clinical of and et al, 2008). of are is that the not and can be to as the of not is less a grade two is to individual as of The of evidence is as high low this in it is to the of and is very to in the of evidence from may well have an on in the of and may the evidence from with lack of to to to to very evidence from studies very and of the of a treatment of a is to have an on in the of and is to the evidence from UK clinical for patients with MCL can be found