Diagnosis and management of mantle cell lymphoma: A British Society for Haematology Guideline

Abstract

The objective of this guideline is to provide healthcare professionals with clear guidance on the diagnosis and management of patients with mantle cell lymphoma. This Guideline was compiled according to the BSH process at https://b-s-h.org.uk/media/16732/bsh-guidance-development-process-dec-5-18.pdf and represents best practice in both teaching and district hospitals in the United Kingdom. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate the levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. Recommendations included a systematic review of published English language literature from publication of previous British Society for Haematology (BSH) Management of Mantle Cell lymphoma Guidelines 2018 up to 02/2023. The search was limited to English language publications and conference abstracts. Titles/abstracts obtained were curated and manually reviewed by the writing group who conducted additional searches, using sub-section heading terms. In addition, there are some further pertinent references and a consensus of expert opinion where no published data are available. PubMed, MEDLINE, Embase, Cochrane databases and Web of Science were searched using the preliminary search terms: MCL OR Mantle Cell lymphoma OR aggressive Mantle Cell lymphoma OR indolent Mantle Cell lymphoma. Systematic reviews, meta-analysis including guidelines from other countries, prospective clinical trials, observational studies, that is cohort or case–control studies, expert reviews and opinions, and case series of >10 patients were considered and reviewed as appropriate. Review of the manuscript was performed by the BSH Guidelines Committee, Haemato-Oncology Task Force, Haemato-Oncology sounding board of BSH. Mantle cell lymphoma (MCL) has a heterogeneous cellular origin, corresponding to the subsets of mature B cells in the primary lymphoid follicle and the mantle area of secondary lymphoid follicles. Most cases are pregerminal in origin, characterised by few/no immunoglobulin heavy chain variable (IGHV) region gene somatic mutations. Approximately 15%–20% are postgerminal centre in origin and associated with a higher somatic IGHV mutational burden.1-3 Classical MCL involves nodal and extra-nodal sites, including the liver, spleen and the gastrointestinal (GI) tract. A non-nodal leukaemic form with indolent and aggressive variants are described.4 Nodal architectural features include classic, blastoid, pleomorphic, marginal zone-like and small cell types.5 Blastoid and pleomorphic types are associated with poorer survival.6 TP53 genetic aberrations are the strongest predictors of poor responses to chemoimmunotherapy, early disease progression and mortality.7, 8 Nodal and bone marrow (BM) tissue should undergo histomorphological, immuno-phenotypic and genetic analysis (Table 1). In cases with an immunophenotypic profile for MCL which are cyclin D1 negative by immunohistochemistry, fluorescence in situ hybridisation (FISH) should be undertaken for CCND1 rearrangement and if this is negative, further studies for CCND2 and CCND3 should be undertaken.9 Routine karyotyping is of unclear clinical value and should be confined to clinical trials. Flow cytometry Standard panel should include CD19, CD20, CD79b, CD5, FMC7, CD200, CD10, CD23, surface immunoglobulin Immunohistochemistry Standard panel should include CD20, PAX5, CD10, BCL6, CD5, CD23, cyclin D1, SOX 11, Ki-67 Patients should be assessed for B symptoms, hepatosplenomegaly and lymphadenopathy, including Waldeyer's ring, and for neurological and GI symptoms. Eastern Cooperative Oncology Group performance status (ECOG PS) and fitness for immunochemotherapy should also be assessed and frailty identified. Blood tests should include a full blood count with blood film, biochemistry including urate and lactate dehydrogenase (LDH), and human immunodeficiency virus (HIV) and hepatitis B/C virology. Echocardiography should be considered, and fertility counselling/preservation offered where relevant. There are no specific MCL-based assessments in MCL, and recommendations are typically extrapolated for frail diffuse large B-cell lymphoma (DLBCL) patients. Frail patients have poor outcomes if treated with intensive chemotherapy,25 making it important to identify frailty to optimise reversible problems and facilitate discussions about treatment intensity and prognosis. Formal frailty assessment tools are preferred over informal methods as they are more sensitive.25 The Geriatric 8 screening tool is a 3- to 5-min screening tool for frailty.26, 27 The Cumulative Illness Rating Scale for Geriatrics and the Geriatric Assessment in Haematology, a 10–15 min tool specifically developed for haematological malignancies28 can be considered on a case-by-case basis and within clinical trials. Current international guidelines recommend fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (18F-FDG PET/CT) to stage FDG-avid lymphomas, including MCL29, 30 on the basis that the higher accuracy of PET/CT versus conventional CT changes staging in ~20%.31, 32 PET/CT is most accurate for detecting nodal and splenic involvement33, 34 and higher standardised uptake value (SUV) rates correspond with more aggressive variants.34, 35 Although specificity remains high, PET/CT has lower and variable sensitivity for detecting extra-nodal involvement; a recent meta-analysis reported an average sensitivity of 36% compared to BM biopsy and an average sensitivity of 39% compared to endoscopy ± biopsy.32 The prognostic role of baseline and interim PET/CT remains uncertain.33 End of induction PET/CT assessment is associated with improved survival outcomes for patients achieving complete metabolic response,32 including those undergoing autologous stem cell transplantation (ASCT) consolidation.33, 36, 37 The BM is the most commonly involved extra-nodal site (50%–90%) and as PET/CT has low detection rates,29 a routine BM biopsy ± aspirate should be considered in all cases for histological and immunohistochemical examinations. This is usually sufficient to identify infiltration38 with ancillary multiparameter flow cytometry in cases of uncertainty.39, 40 BM evaluation for minimal residual disease (MRD) assessment is evolving41 but not yet standard practice. Approximately 15%–30% of patients have symptomatic GI involvement42 but routine endoscopy rarely changes management43 and should only be considered for symptomatic patients or when radiotherapy is planned pending confirmation of early-stage disease (see later section on early-stage MCL). In these cases, only upper GI endoscopy should be considered on the basis that PET/CT has low concordance with endoscopy for gastric involvement but sufficiently high concordance for colorectal disease to obviate colonoscopy in asymptomatic patients.44 CNS involvement at diagnosis is uncommon.45 Lumbar puncture with cerebrospinal fluid (CSF) analysis (cytospin and immunophenotyping) and craniospinal magnetic resonance imaging (MRI) is only recommended when there are concerning neurological signs or symptoms. CSF cellular morphology and immunophenotypic features are similar to peripheral tissue (Table 1). False-positive results can occur from peripheral blood contamination in leukaemic MCL. Several prognostic models are described (Table 2). These models are typically validated in patients receiving first-line treatment in clinical trials and should not be used clinically to influence when frontline therapy is initiated in routine practice. The independently validated MCL international prognostic index (MIPI) can be readily applied. MIPI was predictive of overall survival (OS) and progression-free survival (PFS) for patients treated in the MCL2 trial.46 Weighted sum of 4 variables: 0.03535 × age (years) + 0.6978 (if ECOG >1) + 1.367 × log10 (LDH/ULN) + 0.9393 × log10 (WBC per 10−6) Sum of points: Age: <50 years = 0 pt; 50–59 = 1 pt; 60–69 = 2 pt; 70+ = 3 pt PS ECOG: 0–1 = 0 pt; 2–4 = 2 pt LDH (/ULN): <0.67 = 0 pt; 0.67–0.99 = 1 pt; 1–1.49 = 2 pt; >1.50 = 3 pt WBC: <6.7 = 0 pt; 6.7–9.9 = 1 pt; 10–14.9 = 2 pt; >15.0 = 3 pt Weighted sum of 5 variables: 0.03535 × age (years) + 0.6978 (if ECOG >1) + 0.02142 × Ki-67 + 1.367 × log10 (LDH/ULN) + 0.9393 × log10 (WBC per 10−6) Low risk = score ≤5.70 (44%) Intermediate risk = score 5.70–6.19 (35%) High risk = score ≥6.20 (21%) Low risk = score 0–3 (NR) Intermediate risk = score 4–5 (NR) High risk = score 6–11 (NR) Low risk = score <5.70 (28%) Intermediate risk = score 5.70–6.49 (47%) High risk = score ≥6.5 (25%) Low risk = low-risk MIPI and Ki-67 < 30% (36%) Low intermediate risk = either low-risk MIPI and Ki-67 ≥ 30%, or intermediate-risk MIPI and Ki-67 < 30% (34%) High intermediate risk = either intermediate-risk MIPI and Ki-67 ≥ 30%, or high-risk MIPI and Ki-67 < 30% (21%) High risk = high-risk MIPI and Ki-67 ≥ 30% (9%) Median OS: Low risk = NR (5-year OS = 60%) Intermediate risk = 51 months High risk = 29 months 5-year OS Low risk = 81% Intermediate risk = 63% High risk = 35% Median OS: Low risk = NR Intermediate risk = 58 months High risk = 37 months Median OS: European MCL Younger and Elderly cohorts: Low risk = NR Low intermediate risk = NR High intermediate risk = 52 months High risk = 18 months GLSG1996/GLSG2000 cohorts: Low risk = 113 months Low intermediate risk = 59 months High intermediate risk = 38 months High risk = 22 months Low and intermediate groups do not separate well (and nearly half of patients were in intermediate-risk group) Need to calculate Ki-67 precisely by counting 200 cells at high power in 2 separate areas, not estimation (https://link.springer.com/article/10.1007/s12308-009-0036-x) A simplified version, s-MIPI, has also been described, as has a biological MIPI (MIPI-B) score which incorporates Ki-67, and the combined MIPI (MIPI-C)47 which allocates equal weighting to MIPI and Ki-67 scores. The discriminatory precision of MIPI-C appears better than the MIPI but requires validation. Limited stage disease represents approximately 5% of MCL, and evidence to guide practice remains limited. Localised radiotherapy (RT) is associated with high response rates and some responses appear durable.49, 50 Late relapses, often at distant sites to original disease, are reported in case series where patients did not have comprehensive staging investigations, and stage disease at diagnosis was is considered on this and BM biopsy should be considered to treatment to stage have described small of early-stage MCL with The are small to but outcomes appear similar to those receiving asymptomatic patients to the associated with appears a patients who are and typically years of intensive induction and the standard of Several induction have been including and 3 of by 3 of and of and × 4 ± × specific induction is with overall response rates of and complete response rates of in the induction has in a OS in the MCL Younger of versus and is to separate the of intensive induction from those of Several studies intensive induction with rates of and OS rates of In the MCL Younger with the a validated of improved Although responses are there is evidence that this is for most patients it is that a small of low-risk low-risk patients years and a A of with no clear survival was in the MCL2 in and intermediate-risk MIPI in at for 3 years and and OS were and for those receiving versus and in the group and remains a recommended standard of prospective has compared to as induction with or The was months in the versus months with with no OS years there was and OS in the this was to of patients high-risk MIPI with no on patients with morphology or on TP53 There is no with and or and commonly The assessed can be intensive induction by including the Patients were to by by and A + or by reported that A was not to survival = that is not when is used with induction and for Patients with MCL were included in the studies and were associated with with the of A analysis of the MCL2 and trials outcomes for patients with TP53 planned for intensive induction and The was only months as these patients should be considered for clinical trials practice recommendations for transplantation and cellular in the first-line recommend of in patients with a TP53 who or induction poor outcomes as no specific is available. also recommend as therapy or in the of a clinical The for disease in this is The European MCL Elderly compared and with in MCL over years and of induction OS years was associated with a of but to progression improved the from to years compared to studies in indolent lymphoma including MCL a for compared to studies were conducted for was in a large evidence a role for with in OS and to treatment in patients receiving an response to In a to in a OS was at a of months and was associated with is not or in this in the United Kingdom. and compared to but is associated with haematological OS was this was conducted in a and and is to to results with or by is for and and represents a for there is no evidence the of The of to on on to high response rates in the first-line an of and OS of The is associated with and haematological and as should be considered in patients either for but considered in for years or those years and considered for is in with in the the value of and in high-risk patients with MCL, with the and results The compared with and a of an in in the OS was OS There was no clear in or high-risk MIPI Although was for to be to the on was only 2 patients to an compared to and more was was also associated with more The is not or in the United Kingdom. trials with immunochemotherapy are The of by and versus or by is and with and and versus are in first-line MCL patients. Frail patients with including MCL, more and have outcomes than patients. In cases, patients of and over patients planned to should be to where disease is performance as well as a to optimise treatment include and and or in with patients treated with for up to 8 months reported an of of 36% and a of of patients who for a by months of reported a of series included patients with low-risk MCL. MCL patients considered for or who or The was and on the analysis of patients receiving than those on but more There was no OS the treatment include and first-line trials clear of and OS rates of and and (5-year and OS rates of and with disease Although these be in patients with the trials performed were not specifically in this cohort and is in the United Kingdom. in some cases, best be either or of MCL can be clinically and and for of all MCL Several studies that these patients can be or MCL typically with peripheral blood and splenic and from B Nodal MCL can also with small nodal disease with a low Ki-67 or and can an asymptomatic This group of MCL patients have outcomes with The MCL that was more than Approximately at 1 and at 2 years from LDH and a high Ki-67 were more in patients other studies that for a nodal and non-nodal MCL, is and can have data are the of genetic features as TP53 or on to recent small prospective trials of and have disease in low the of of 2 years of and the to progression and high and rates These be considered if for in the of a clinical In the or therapy be assessed in this specific patients first-line the routine of a is in clinical practice and data have this with improved in patients are considered for cellular it is recommended that risk profile is assessed This should include a for assessment of TP53 status and a of patients do not to and for this group is patients should be with a centre and early response assessment is recommended to to therapy in the recent BSH high-risk patients should be for clinical trials. progression of disease first-line treatment is associated with outcomes on as a that is within months < within months < no This recent data survival outcomes for patients on a can be according to a clinical and MIPI at diagnosis The 2 MIPI groups with including high risk intermediate risk and low risk to Ki-67 and MIPI are associated with survival outcomes in patients with MCL receiving 2 clinical models these in for as stem cell transplantation or with of The and have and and has and and European for in (Table high response rates in a cohort in a and in a compared to months < A analysis improved in patients receiving at compared to later months in the treatment The of to has also been assessed in a small rates appear improved but the of these are limited by the small of high-risk patients for the and in MCL is the results of 81% and with a of 22 and with a of studies to have compared the and of the in MCL. the in and the methods of response assessment studies, it is unclear in and rates are Although not with MCL, studies in and outcomes of to or improved profile for the with rates of and is the only by the In recent clinical trials and early have to first-line therapy but routine is not available. Management of in this a first-line is not but include the of standard and have high response rates in studies in MCL and over in MCL patients at In a a of months in a MCL cohort and appears to are in the United at an autologous has been by the for MCL of including a The reported responses and with of patients in response at a of ≥ 3 included neurological and by in for treatment in and is reviewed by the using criteria (Table A similar in of at that and outcomes for those are with prospective analysis the of disease at with a and guidance a for at with the of those at high risk of early and early or disease in patients is not an A of MCL in the CNS is not an at of centre and are not an BM × × × if BM involvement with MCL patients should be with a centre at and at in the 3 Patients with no 4 of should be considered for early high-risk patients should have imaging response assessment as early as 8 but no later than response of disease 8 of or should an to a centre 1). at the of some risk of the of therapy to patients. of at this stage should be to risk of of disease be to and where should be to on therapy is as treatment and and of as radiotherapy or other as and or in these are in the United Kingdom. practice of heterogeneous of published and in cell and to outcomes in patients receiving but also an the of and high-risk disease the of achieving disease and ECOG PS to cell practice to of patients with where a to a in and of extra-nodal sites and ECOG PS with survival and this to MCL, disease be to the but also to optimise the of and of In the of MCL patients are receiving with poor of the for more predictors of therapy in MCL are responses in high-risk disease in but small for patients with poor prognostic has for those with high-risk disease as high-risk Ki-67 ≥ TP53 and The reported = found age ≥ ECOG PS high-risk disease and were associated with which remains the most of patients intensive for a of 3 and was at 1 of of of are important in an the of response and of and appear to studies with a more profile also be for therapy should be in with with a on and 3 and was in and and is recommended for at 1 and count × therapy is considered in patients with secondary and the of evidence and the high of lower the risk and of for patients who or are for or for are Patients with poor ECOG PS best as data than half further A of trials are in this but no standard of is for immunochemotherapy are limited to small studies, the patients receiving and rates were high with a and OS of and months to in nearly all patients over with in of the and B-cell is the most clinically MCL patients with have been with of and the 52 was 22 appear limited and rates of and were is with at or later Several other are clinical but only is in studies in MCL, treated to are is a results reported high and a of months in studies of in MCL patients a of months most are in the disease and a has to a in is an the patients there were responses with a of and peripheral were the most cells to cells and in B-cell is specifically in MCL, using standardised and In a 37 with have been a of 8 the was was and was patients treatment to rates of There are limited data on MCL patients treated with the and to A of 58 patients using an of with a of The profile was but the limited and of responses is and are for MCL to a of low responses and of data be Limited data for in response are in and prospective and low rates are were by high rates and disease to for MCL was used in patients with a achieving with the of high and data to therapy over are not but international consensus is to therapy where on high response rates with therapy of in high-risk MCL including low and an to therapy with for are confined to studies of 22 patients a of and 5% and of patients who also with a of There are no published studies therapy at Although is a for patients including and the of patients be small to a of the age of patients receiving of disease and the for a can be to in patients to where the of is in and cell to disease, to high-risk there are data to recommendations on which patients be of and to further the of cell therapy in MCL. for patients with an and of MCL is and remains typically at a of at with a to of The of involvement is than A higher risk is in patients with high ECOG PS and high MIPI is unclear used in treatment as or influence this CNS MCL involvement is a within prospective clinical trials, and as the evidence for management is primary limited to case is to the CNS and a recent large international series that response rates and survival are to is about the of or the in this data of treatment in patients CNS disease a Although cells are within the CNS and there are small and clear in with CNS there is only a case of a MCL with CNS disease treated with within the to data with therapy are recommendations can be reviewed the literature and to the and of this and the BSH Guideline and was for the The to for in the literature The BSH Haemato-Oncology Task at the of writing this guideline were and The to the BSH sounding board and the BSH guidelines for in this The BSH the the writing of this have a of to the BSH and Task which be on of the writing group the writing group if pertinent evidence that the strength of the recommendations in this or it The be and from the BSH guidelines if it recommendations are an be published on the BSH guidelines the and in this guidance is to be and accurate at the of to the the the for the of this

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