The investigation and management of follicular lymphoma

Abstract

Follicular lymphoma (FL) is a heterogeneous disease. For many it is experienced as a chronic, relapsing, indolent condition with long overall survival (OS). Most people affected have advanced disease at presentation; symptoms may include B symptoms (i.e. fever, night sweats and weight loss), fatigue and the local mass effect of lymph node enlargement. However, many people are asymptomatic at presentation. Some people are observed without treatment according to a ‘watch and wait’ policy (see section Management of patients with newly diagnosed FL). In contrast to this, over a period of many years, 20–30% of patients will die from refractory FL or following transformation of their disease to high-grade lymphoma.1 Prognostic indices may help discriminate between risk groups (see section Prognostic factors in FL). Survival of people with FL has improved over the last 30 years. Single-institution series show up to 30% improvement in 5-year OS.2, 3 A USA population-based registry study of >14 000 patients between 1978 and 1999 showed an increase in median survival from 84 to 93 months.4 Improvement in failure-free survival (FFS) was only seen following the introduction of anti-CD20 therapy given in combination with traditional chemotherapeutic approaches. Treatment plans for an individual person should be part of a long-term strategy and planned after multi-disciplinary team review with lymphoma specialist clinicians and nurses, specialist haematopathologists, radiologists and radiation oncologists. Numerous treatment modalities are available, but some may compromise future choices. Risk of long-term complications, such as myelodysplastic syndromes, other secondary cancers, cardiac toxicity and effects on fertility must also be considered, given the extended and increasing survival of many people. Psychological support from clinical nurse specialists as well as other bodies, such as patient groups, is particularly important in the face of the chronic relapsing nature of this disease and the multiplicity of treatment choices available to the person affected and their physician. This document represents an update of the inaugural British Society of Haematology guideline, published in 2011, which now merits an update due to significant developments in the understanding and therapy of the condition. FL is a B-cell neoplasm derived from germinal (follicle) centre cells. Involved lymph nodes show replacement of the normal architecture by closely packed neoplastic follicles that are uniform in size, lack tingible body macrophages and possess poorly formed mantle zones. Reactive germinal centres contain a mixture of centroblasts and centrocytes organised into well-defined zones, whereas germinal centres in FL contain a monomorphic population (usually of centrocytes) and lack any evidence of zonation. Whilst most cases show a uniform pattern of closely packed follicles throughout the involved tissue, the architecture of FL can be variable. In some biopsies there is a mixture of follicular and diffuse areas and in rare cases the architecture is completely diffuse and lacks any identifiable follicular structures. Approximately half of all FL cases show bone marrow involvement at presentation.5 Follicle centre cells express B-lineage markers and the germinal centre cell antigens CD10 and B-cell lymphoma 6 (BCL6). The interfollicular component of the node and bone marrow disease often shows down-regulation or loss of these markers.6 The underlying networks of follicular dendritic cells can be shown with CD21. Normal germinal centre cells are BCL2-negative; in 85% of cases the neoplastic cells in FL are BCL2-positive. At the molecular level, FL shows a characteristic t(14;18)(q32;q21) translocation which relocates the BCL2 anti-apoptosis gene so that it is adjacent to an immunoglobulin promoter, leading to over-expression of BCL2 protein. The tumour cells in FL show light chain restriction. All cases of FL require a histological diagnosis. A fine-needle aspirate is inadequate for the diagnosis; whilst FL cells can be detected in cytology specimens,7 with confirmation by polymerase chain reaction, fluorescence in situ hybridisation and flow cytometric immunophenotyping, histology is needed to grade the tumour and to exclude transformation to diffuse large B-cell lymphoma (DLBCL). Appropriate investigations following diagnostic biopsy in FL serve a number of purposes. Staging investigations enable an initial assessment of disease extent, including determination of the stage of disease, identification of sites of bulk disease and derivation of prognostic scoring systems, such as the Follicular Lymphoma International Prognostic Index (FLIPI and FLIPI2). Baseline staging also provides a rational basis for treatment, allows appropriate disease monitoring, and facilitates comparative post-treatment assessment. Functional and anatomical imaging with FDG-PET/CT, utilising the labelled glucose analogue 18FDG, has become a standard-of-care investigation for several lymphoma subtypes. There is substantial evidence that most cases of FL are visualised on FDG-PET/CT irrespective of grade.8-13 FDG-PET/CT is the imaging technique recommended as the standard for staging FDG-avid nodal lymphomas in the Lugano classification.14 FDG-PET/CT in FL may detect additional nodal and extra-nodal sites of disease, compared with standard CT assessment. One retrospective study was performed on 45 patients with untreated, biopsy confirmed FL who underwent FDG-PET/CT and CT before and after immunochemotherapy induction (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone). FDG-PET/CT detected more nodal (+51%) and extra-nodal (+89%) lesions than CT. FDG-PET/CT modified staging in eight patients (18%). Five patients (11%) initially considered as limited stage (I/II) were upstaged to advanced stage (III/IV).15 Specifically, sensitive FDG-PET/CT staging of clinical stage I FL may contribute to the improved prognosis in patients treated with involved field radiotherapy compared to historical cohorts, likely due to better identification of true stage I disease.15, 16 Recent studies, of variable quality, suggest that up to 45% of people with what is thought to be limited stage FL are upstaged by FDG-PET/CT compared with CT. There are currently no studies reporting on the influence of FDG-PET/CT on FLIPI risk stratification.17 There are specific limitations of FDG-PET/CT in FL. It is of limited value for the detection of bone marrow disease; if documentation of marrow involvement is important to the person’s ongoing management, then a bone marrow biopsy is required.11, 18 Despite widespread views to the contrary, semi-quantative analysis of uptake does in of FDG-PET/CT for FL In FL as a shows uptake compared with but significant the histological grade and with disease. FDG-PET/CT is but CT is also It should include the and and from the to the of the is In FDG-PET/CT is the staging for FL. CT is an In to imaging to the of disease and areas of other investigations are to underlying and and prognostic The for some may according to A and clinical should be to significant and such as the and of may be in bone marrow and biopsy has recommended to in clinical more for prognosis (see section Prognostic factors in FL). However, for staging FL is it will For if the is for initial it is to the treatment or into a clinical additional of stage a is flow on the aspirate to a germinal centre B-cell population bone marrow involvement and the for if flow is performed but by is in the biopsy then this is for a of bone marrow involvement in an of FL and is A to an initial bone marrow biopsy may the to prognostic but the should be the and and of the (see is and should be considered in people with a of cardiac disease including disease, or The of any treatment on fertility should be with and to that the median of of FL is this is to be a for most people. However, if should be and of should be to an to that the studies are are part of prognostic scoring or effects of lymphoma or are part of the assessment B In an study prognostic factors in patients with FL in the of the This the following years, than normal value of stage and involved nodal The FLIPI patients into groups and well in of the of patients in and with and well as prognostic the FLIPI also people with a risk of histological In an to on the a has utilising from newly diagnosed FL patients the following factors for survival than of normal bone marrow years, and lymph node This analysis was that were from patients treatment that the FLIPI was in the a large USA study has shown that the FLIPI in the immunochemotherapy and as well as The FLIPI and were as a analysis of the this a scoring was bone marrow involvement and This risk groups with 5-year of and However, this has only in the of treatment with immunochemotherapy and all patients to a Prognostic at are well on the value of FLIPI at the of are to survival from has confirmed in retrospective FLIPI and prognostic for patients treated with FLIPI or should be and at for all patients in clinical The FLIPI has to for patients with FL has only to prognosis and treatment in a clinical However, on clinical the for and has now the of FLIPI in a treatment section on Management of patients with newly diagnosed FL). there has a prognosis on assessment the of initial following Prognostic survival at or of disease or the of a with therapy at 30 All of these are with is also with A of in the of therapy have to disease which may the with following initial therapy may to a more including (see section in particularly in patients and an for clinical staging is recommended for a stage disease considered for including CT and to exclude advanced disease, which require stage FL stage disease, the involved nodes are and can be a radiation has treated with local FL is a lymphoma and a number of series in the a with of patients long-term disease at and of the of in these patients that most the FDG-PET/CT a significant number of compared to in patients by have in an to if more staging to better patient and suggest in the the following radiotherapy for stage I and stage FL after staging is better than in historical than of patients in at and most in stage patients were with a from radiotherapy has become as the the radiotherapy the a in in The in was the more radiation for stage indolent lymphoma lymphomas as well as with improved local of this was in the treated with there were after and after The in should the of for radiation therapy in FL. However, in with other published studies, in was with or no toxicity and a for treatment without can be considered in people with limited stage FL who have and there may be by the or patient radiotherapy to a that stage disease that is or for radiotherapy should be as advanced stage disease. studies of have shown that there is no to treatment in patients with advanced stage asymptomatic FL compared with a in of and In the study of patients with 16 of the for patients for a ‘watch and wait’ were as the of the or B disease in the 3 significant bone marrow in bone marrow to bone and significant disease was an A more of which tumour were by the as for tumour was nodal or extra-nodal mass nodal sites with a of no no substantial no risk of and no or have modified in studies over the and now of B symptoms and normal and A between the modified and the of tumour is that the no more than nodal sites with a the of the of tumour study In clinical a does to be limited to patients with tumour it is likely that patients with a tumour will have a disease is to the of therapy by In the of patients of lymphoma at after study This to in patients years. there is for treatment in patients with advanced asymptomatic FL. who have an risk of high-grade compared with who treatment The of a is that the of are or of a study in patients with advanced asymptomatic FL compared with treatment with the standard induction or the induction by for years. were after a median of The was to of At 3 after of patients in the ‘watch and wait’ whereas of people in the induction and of people in the induction and The between the was There was no in with of all patients at 3 years. of was in most patients with no in the in of were only seen in some in the induction and such as people more in of their and their disease more or to support and their A analysis by the Lymphoma in to induction and induction by were with induction the strategy of induction for people with FL who are This is particularly in patients will be due to other that is in the for of advanced stage asymptomatic FL and is for this by The of to induction a in the of and the only to an improvement in in patients with on these it is that an anti-CD20 should be to in the treatment of advanced FL but there is as to which it should be has compared with and cyclophosphamide, vincristine and in the of of on and of a significant improvement in compared to the for the was than have from other studies was with a of and a compared to has the in from the which of compared to with cyclophosphamide, vincristine and or with an improved overall in the the after induction (see have many clinicians to over or as the of The and have of but the of with is for the widespread uptake of this the toxicity with compared with this combination is it is important to be of the risk of significant and Whilst there is evidence to support of should be for in which high-grade transformation is confirmed or (see section on FL or with is in patients for the of are thought to be For many will be the of The of is on and of for up to but this can be to or the can be in patients a on of or All patients must and and should be given to support of the The may be to the of is an anti-CD20 with than In the patients were to or or by of in There was a significant improvement in with The important of was also in the and other the including disease more as well as in in the There were more with compared with these were but there was also a increase in the of and that the of was many including of disease, and There was in patients with a FLIPI in for patients with advanced stage FL with a FLIPI of to be with the treatment due to the risk of and is treatment and for and is currently available in a that can be that patients require The showed that of with to a significant improvement in that this is with of patients in the have of therapy at years. However, has on of the lack of and the of in patients The value of or after induction has in a and the of after were in the of which was (see However, a by in that there is a of after with a of to that seen in the with the anti-CD20 that was in induction should be considered for patients a or to induction is for years. to be the and In patients who have experienced induction it may be appropriate to There must be a for in people who There is no for immunoglobulin The of was by in for the and is now of people with FL who have of the therapy or who are to and an have the This represents the of in FL. In the the effects of may be particularly to the choices of therapy and is is the with the at the of has The to an combination should be on patient such as cardiac and the of For patients who have following treatment may be with an combination This is on the seen with this in the of and from due to in the of the disease or if transformation In patients who are to or who have following or who have to their should be studies show that most people who following immunochemotherapy will this at the of It should be that of patients with is in patients who have disease for people with disease are more limited for who are to people who or who or 6 after treatment with or a There have several developments for people in this has with a median of in A 3 has evidence for a of (see section Management of patients with newly diagnosed with and by for years, compared with The was with and compared with with in In the of with was than with The number of patients who following induction was The combination was with an increase in and compared with The in with this has to into an in a is a of The is for and survival of B cells and is in FL. At a of or are observed in 45% of people with FL who have including who are and with the median to be 16 analysis also in 3 include and has as in the the and are improved with the of It is recommended that patients who require therapy be treated with the combination of and For patients who are of due to or for other with can be for up to following a to has a a that and in disease, after induction in people who have a as that treatment has in the of in therapy and it should be for patients who their The of in the for who in the is has in the and refractory It can be as a therapy in people with significant and of treatment with are for treatment of or refractory and However, it is important to that and centres are to and has limited by in the FL treatment and as long-term and the on treatment radiotherapy should also be considered in the of FL in clinical therapy is are and toxicity people with FL should be considered for therapy with cell after a or This is in the section in FL. a in the of the cases histological transformation in patients with FL in a lymphoma that is and from so patients should be treated according to for The of transformation at or is the of these as should be as In a patients with who have no or who have only should be treated as with immunochemotherapy without studies have that patients who have to transformation and at the of better than treated with some series have also shown that the of patients with who to and this at transformation is to that of patients with treated with the patients who were a better than who treated with patients for for the treatment of treatment with is with a after in some whereas in other series to is with a after for but after for The treatment of patients with to with or without is in for in patients who are for with in the there is no evidence that is to the the of patients with in the the was to the with in from registry studies show that the of patients who for lymphoma is to that of patients who for an indolent lymphoma or for an However, in the does in a better than in patients treated with for in treated the of as part of the of is with a better in of retrospective studies have an of over the of to patients who have treated for FL or and who have The of patients for should on a at a with of these patients should be in clinical if with have from the of in patients with FL. The of in patients with has in several after initial therapy with or after In of these studies the of in a better the study performed by the patients with at A retrospective study from the British the of patients with or lymphoma according to or after There were no in or the groups of immunochemotherapy at have performed in patients to the evidence in the from retrospective have body was and secondary were in This is A number of in FL. these studies are to given their retrospective variable of and number of of treatment and these studies, patients are than the FL population-based in more FL is the patients in the studies is with of and of is with a and a of secondary suggest a at 5-year in in their treatment have an improved and In a standard in with improved performed at 3 and due to in at at 6 registry registry or or or 45% 5-year All patients were treatment 5-year registry and or or or 5-year All patients were treatment 5-year than no at at 3 and factors for and and and up study from and registry 5-year at at with for 5-year 5-year in registry 5-year at at refractory disease and were with a of registry or or 5-year All patients patients only registry or or 5-year All patients 3 patients only retrospective 3 5-year cases for after than Recent retrospective series have the of in patients with treatment also following A survival analysis compared patients treated with a with patients A planned analysis showed with of treated with 5-year than with a A analysis showed a significant and for in patients 5-year from these the evidence that is an in provides a of with the to a as the was with a of and a of with a and of and The risk of and chronic disease is to studies given the variable reporting of and it is to be and The series of patients showed a and of and with a of and a risk of patients with and an 3 3 6 3 3 There are with in FL. the evidence is formed from retrospective studies these in FL and more in analysis by the Society for and compared with as in FL were disease after was by the compared to for was improved for risk 5-year for for with a However, this in an The therapy for patients who after an is in patients an are more with of studies reporting The study patients 45 median who an at a median of 30 to the The was with no according to The 5-year and were and after and is to disease with an survival compared to in the The large between and patients as in no 5-year between and were to 5-year for an by 5-year was with these suggest that or is a in particularly in between the modalities represents an ongoing The long-term disease to be with the risk and of chronic and evidence represents an to or The risk of this is and assessment. with have an survival to the normal and as such to should be for with a to years, the evidence for such patients is have an in the of with several or in of clinical including anti-CD20 of and and of the is involved in the and of and lymphomas and is a prognostic in this are the most for FL. than in section with USA and for or refractory FL include the and and the with in the and was on of for and for in and patients with FL The were and with specific The and showed in patients with in a with a of compared to other important of is that treatment disease or and is an with and of and toxicity was in of or refractory indolent lymphoma and to several combination A of or in combination with in patients with FL overall of and for and and B of and in FL of and and treatment was well The was a 3 to of compared to A of patients with tumour FL were to or or over a The to show of and was to there was no in the of the toxicity between there was a of but more and more with and was more with Whilst this may have a in the future in the of advanced stage it is currently in the and is needed to as A more 3 of and in or refractory indolent patients with for and it is these will in the is to FL. The of therapy is an and important for with of B-cell including with in the treatment of with FL is There is no strategy for patients is at the of symptoms or significant disease The of after initial is by the of disease For most that up to of people with FL will but have therapy at after diagnosis. It is important to have a in for people with FL to the if symptoms that suggest disease At an symptoms should be as well as a may for therapy are is as this is an to therapy and may and is most to is the of lymph node that the of therapy if the patient The Management of patients with newly diagnosed are important in the to to in the of of there are no standard for patient after The of and the to disease should be to the individual disease and as well as treatment imaging should only be considered if the disease is to by clinical but asymptomatic disease may imaging the Approximately of treated patients a of and have a and survival to the normal it is important to on to these patients to to with a lymphoma over many years, which will an this in long-term effects of must also be considered in the treatment or to be for the of and the effects of The to for help in the initial The at the of this were and The to the and the for their support in this The the the of this All have a of to the and which may be on of the have of to of the will the if any evidence available that the of the in this document or it The document will be and from the if it are an will be published on the the and in this is to be true and at the of to the the the any for the of this

Topics & Concepts