Guideline for the management of mantle cell lymphoma

Abstract

This guideline was compiled according to the British Society for Haematology (BSH) process at www.b-s-h.org.uk. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) nomenclature was used to evaluate levels of evidence and to assess the strength of recommendations. The GRADE criteria can be found at http://www.gradeworkinggroup.org. MEDLINE, EMBASE, DYNAMED, TRIP and NHS EVIDENCE were searched systematically for publications in English from 1980 to 2017 using the Keywords ‘lymphoma’ and ‘mantle cell’. References from relevant publications were also searched. Editorials, studies with <8 cases and letters were excluded. Conference abstracts have been included if deemed to be of particular relevance. Review of the manuscript was performed by the BSH Guidelines Committee Haemato-oncology Task Force, the BSH Guidelines Committee and the Haemato-oncology sounding board of BSH. It was also placed on the members section of the BSH website for comment and has also been reviewed by patient representatives identified by the Lymphoma Association; these organisations do not necessarily approve or endorse the contents. The aim is to provide healthcare professionals with guidance on the management of patients with mantle cell lymphoma (MCL). Individual patient circumstances may dictate an alternative approach. This is an update of the guidance published in 2012 (McKay et al, 2012), incorporating new therapeutic options, including transplant data. Developments in pathology, in particular molecular pathology and use of positron emission tomography/computed tomography (PET/CT) scanning in staging and response assessment are now covered in a separate Good Practice Paper (McKay et al, 2018). Mantle cell lymphoma (MCL) is a B cell malignancy with unique biological, pathological and clinical features comprising 3–10% of all non-Hodgkin lymphomas (NHLs) (Swerdlow et al, 1983). It was recognised as a specific entity in the revised European-American classification of lymphoid neoplasms (REAL) classification (Harris et al, 1994) and is characterized by the chromosomal translocation t(11;14)(q13·3;q32·33), resulting in over-expression of the cell cycle protein cyclin D1 (Akiyama et al, 1994; Campo et al, 1999). MCL arises mainly in older adults (median age 60–65 years) with a male predominance (Argatoff et al, 1997; Bosch et al, 1998). It often 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 with standard therapy. Historically, median survival was 4–5 years (Herrmann et al, 2009) however this is now in the order of 8–12 years in younger fitter patients who are able to tolerate modern intensive therapies (Eskelund et al, 2016; Hermine et al, 2016). The clinical presentation of MCL is well described (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 disease. Lymphadenopathy is generally widespread at diagnosis. Splenomegaly, bone marrow infiltration and peripheral blood 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 infiltration of breast, lung, skin, soft tissue, salivary gland and orbit are also seen. Involvement of more than two extranodal sites occurs in 30–50% of patients (Jares & Campo, 2008). Spread to the central nervous system (CNS) can occur, but this is rare at diagnosis. The clinical course is heterogeneous. Presentation can correlate with pathological sub-type; patients with blastoid histology often have an aggressive clinical course, show refractoriness to treatment and have short survival. In contrast, some cases present with more indolent disease (Eve et al, 2009a; Martin et al, 2009) characterized by splenomegaly, peripheral blood lymphocytosis, little or no nodal disease (Nodit et al, 2003; Orchard et al, 2003) and survival of the order of 5–12 years. The entity of MCL in situ is now recognized, indicating early foci of disease in otherwise reactive nodes in asymptomatic patients (Carvajal-Cuenca et al, 2012). CNS relapse rates of 4·1–7·8% are reported, with high Ki67 and blastoid histology identified as risk factors in multivariate analysis (Conconi et al, 2013; Chihara et al, 2015; Cheah et al, 2016). CNS relapse tends to occur early (median 15–20 months) and survival is poor (3–8 months). A high incidence of leptomeningeal disease (91% by flow cytometry) has been reported (Cheah et al, 2013) with parenchymal disease being uncommon (12% of cases). Diagnosis, Initial Investigations, Staging and Prognostic Scores – please refer to the Good Practice Paper (McKay et al, 2018). Patients should be offered a clinical trial if available. Assessment of performance status (PS) using the Eastern Cooperative Oncology Group (ECOG) performance status tool is recommended. Geriatric tools, such as the Cumulative Illness Rating Scale (CIRS) and activities of daily living (ADL) assessment may be useful in elderly patients with lymphoma (Nabhan et al, 2012). A minority of patients present with localised (stage 1A and 2A) MCL. Evidence for management of this group is scarce. Involved field radiotherapy may result in good responses with 64–80% complete remission (CR) and long-term remission, with possible cure in some patients (Vandenberghe et al, 1997; Rosenbluth & Yahalom, 2006). If early-stage disease is suspected, staging should be confirmed with bone marrow examination and gastro-intestinal investigations. The role of (18F) Fluorodeoxyglucose (FDG)-PET in early stage MCL remains unproven but may be considered if radical radiotherapy is being proposed – please refer to the Good Practice Paper (McKay et al, 2018). Once treatment is deemed necessary, choice of regimen will depend on age, co-morbidities, performance status and the aim of therapy. Distinction should be made between young fit patients suitable for autologous peripheral blood stem cell transplantation (ASCT), and those for whom this is not appropriate. For those where the aim is to proceed to high dose therapy (HDT) and ASCT in first remission, intensive chemotherapy should be given with the aim of obtaining a complete response. Rituximab has less activity in MCL than in follicular or diffuse large B cell lymphoma. Rituximab monotherapy, although well tolerated, is not recommended, having been shown in several trials to have only modest activity (Foran et al, 2000; Ghielmini et al, 2005; Weigert et al, 2007). Addition of rituximab to chemotherapy, however, improves responses, including CR rate (Howard et al, 2002; Lenz et al, 2005; Schulz et al, 2007). A recently published phase III randomised trial (Rule et al, 2016) confirms survival benefit when rituximab is combined with chemotherapy in first line treatment. CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) (or CHOP + rituximab – R-CHOP) is not as efficacious as more intensive regimens for achieving maximal response prior to transplantation (Lefrere et al, 2002; Andersen et al, 2003; Dreyling et al, 2005). There is increasing awareness of the efficacy of cytarabine in MCL, with excellent responses, overall response rate (ORR) and CR rate, when incorporated into first line regimens. Most studies have shown an ORR of >90% and CR rate of >50%. High-dose cytarabine was first utilized in MCL as part of the dose-intense hyperCVAD regimen (hyperfractionated cyclophosphamide, vincristine,doxorubicin, dexamentasone + methotrexate and cytarabine)with good results in single-arm, single-centre settings (Khouri et al, 1998). Addition of rituximab gave CR rates of 87–92% (Ritchie et al, 2007; Romaguera et al, 2010); remissions appeared durable, even without consolidation with ASCT. The main concern with rituximab + hyperCVAD (R-hyperCVAD) is acute marrow toxicity and infectious complications, and a long-term 5% risk of myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML). Two multi-centre studies (Merli et al, 2012; Bernstein et al, 2013) concluded that while R-hyperCVAD is an active regimen for first-line therapy in MCL, it is difficult to deliver, with almost 40% of patients unable to complete the planned treatment schedule. As a result, hyperCVAD-like regimens are not recommended as a first line approach. High-dose cytarabine was subsequently incorporated into other combination chemotherapies. In the Nordic MCL2 study (Geisler et al, 2008), excellent results were achieved with a cytarabine-containing intensive induction immunochemotherapy regimen by Patients of CHOP with of Rituximab was given from cycle with an dose given as in prior to survival at years was possible but two of this study (Geisler et al, 2012; et al, 2016) have shown a pattern of relapse and no in the survival in the and risk 40% of patients were in first remission at years. In a phase now as the Lymphoma trial et al, cytarabine and rituximab were incorporated into induction ASCT. with rituximab included in cycle and of + high dose patients were for ASCT. ORR was and with more on of was and median overall survival was not at median was The study use of a ASCT regimen induction treatment with of and to and prior to ASCT median of to treatment was in the cytarabine group years) et al, 2016). In the phase trial et al, patients of with if not in remission as induction therapy prior to ASCT with + and to rituximab or induction ORR was a median of median and were not with a years and of and A phase study et al, 2016) induction with of by of dose cytarabine in CR rate was disease achieved was at median of was mainly and was more dose but overall the regimen was well increasing response rate and response of response with remains There an increasing to with high dose therapy and peripheral blood stem cell transplantation in younger This has been shown to and and is in the transplant section The to therapy of blastoid MCL has not been with no studies for this MCL patients however, been included in of the studies reported have identified blastoid as a poor with early and short survival et al, responses in patients with intensive including R-hyperCVAD (Romaguera et al, have been reported, and those therapy using ASCT et al, et al, et al, 2012). The majority of MCL patients are elderly and therapy is not For this is no and it is difficult to a specific Historically, MCL was with lymphomas in clinical studies and with regimens including (cyclophosphamide, vincristine, prednisolone) et al, et al, 1995; et al, et al, and CHOP et al, Lenz et al, 2005; et al, 2006). Most studies included only of The pattern was of ORR but short months) and poor at particular combination appeared in of In the of in the only trial et al, not survival this being confirmed in other studies et al, 1998; et al, CHOP remains a used chemotherapy regimen and the in The efficacy of in MCL has been in the with used as a of are et al, 2005; 2005). when used in combination with such as or cyclophosphamide, response rates to et al, 2000; et al, In to the and toxicity of use may & et al, MCL of with and to of et al, 2012). patients a to treatment with rituximab or was disease response rates were but was with more disease and at years The regimen was with more toxicity in the study by et and is no recommended as first line therapy for elderly patients with MCL. has efficacy in MCL et al, 2005; et al, and having a toxicity to CHOP may have an increasing role in treatment. The combination and rituximab an ORR of in the study by et In the a phase study in indolent including MCL et al, was to or with ORR for and for phase multi-centre study by the group et al, 2013) with as first line treatment for patients with indolent and mantle cell in the group months) at a median of was with less and peripheral although were more common. In a phase trial et al, patients with MCL for were to of or cyclophosphamide, doxorubicin, where was for in the regimen and given at a dose of on and CR rate and but toxicity was This study poor in the to and the of in the and to be an for elderly The et the doxorubicin, and regimen in a phase study of median age years et al, 2012). ORR was with was median not The of may have to the high incidence of of cytarabine in the treatment of older MCL patients is less well et used a combination of and cytarabine in a phase study of patients years. a cytarabine dose of dose in phase the the main toxicity was with in ORR was complete with a of A dose regimen with cytarabine dose was tolerated, with less results of the phase study et al, CR of with and of and The combination has but results to be in has been to in an to In a phase study et al, 2012), patients median age of by consolidation with ORR was and median to treatment was (median months). was The regimen was well with results with reported regimens for elderly patients rituximab combined with et al, 2005; et al, or et al, with overall response rates of to The of therapies to the incidence of CNS relapse is with results reported (Cheah et al, 2013; et al, 2013; Chihara et al, It is not possible to on CNS use of chemotherapy may be in patients with high Ki67 blastoid In some by rituximab has of response but not et al, et al, 2006). In such as the MCL MCL et al, a survival benefit was in to the risk of or by of patients rituximab were in remission years with of patients Patients who well to induction rituximab in CR in In a analysis of the rituximab for years no benefit and to in patients with et al, 2016; A of large clinical trials but not with rituximab et al, rituximab is included as standard in clinical trials and the of to follicular rituximab in patients or to and who are not to ASCT as well as in the It is difficult to an of therapy. In the MCL MCL et al, 2012), treatment was disease however to years. It is that should be in with In the should be for years et al, response in MCL is using scanning et al, 2007). As in the Good Practice Paper (McKay et al, the role of in MCL is not There is increasing evidence that of treatment has et al, 2012; et al, however as this not management do not a at present in the of a clinical disease for the has been shown to have particularly ASCT & the is not at the present and the clinical benefit median survival first relapse of MCL is years. There is no standard line generally and of response is than being of the order of for and publications have therapeutic regimens in including patients with MCL. Most are than the that can be criteria of the relapse studies are it to comment on the patient has not ASCT as part of first-line therapy but is considered fit for such therapy at of consolidation of response with ASCT is a clinical In young patients who have assessment of for an should be If the patient is the aim should be to a response with therapy and with This use of standard regimens as in the of aggressive the of the however, an alternative is active in the majority of MCL and the of response a to and the The majority of MCL patients will not be for ASCT or of therapy will be by age, performance and therapy. It is where a patient has prior line of a be at on the only randomised trial survival benefit et al, combination chemotherapy is given with rituximab in MCL The role of rituximab line therapy is not with only published study et al, MCL patients with + and were randomised between rituximab and no therapy. response was between but a of patients in the remissions years The relapse study of in combination with rituximab included patients et al, ORR was CR was with a median of response of and of The of cytarabine to and rituximab an active regimen in relapse as well as in the line et al, or patients were achieving an response rate and of The activity of et al, is by of et al, and rituximab et al, where ORR was with CR and response in the relapse to response rates of with CR and median et al, 2008). are by the of and rituximab et al, 2006). In a study of patients with disease, was given in combination with or with et al, 2007). ORR was at and but was short at as a is less active than in a study of when was given in combination with ORR was with CR et al, were with a of Rituximab and have been to the a dose chemotherapy incorporating cyclophosphamide, and patients ORR was with of therapy was et al, 2008). Addition of and rituximab to this regimen not to results et al, are for use in MCL, and The efficacy of these as in trials and patients is shown in were with patient the active of these with CR rate and of response. There has been randomised trial these et al, where was with in patients a median of two prior of therapy. There was a with and less but a median of no survival benefit was As with chemotherapy in MCL, have been used in combination with rituximab and the results of these studies are included in is no randomised is a in both response rate and the of rituximab for all and a of A randomised trial of patients incorporated a into standard chemotherapy in the was to standard CHOP in first relapse MCL et al, There was ORR CR rate and in of the was given on a of not even when to of combined with and rituximab et al, and rituximab et al, high dose cytarabine et al, et al, et al, and et al, show response rates but are et the of to in patients with ORR but a median of only is an activity in a of and in MCL has activity of et al, however, be durable, on a with those with rates can be by with ORR et al, 2012), ORR et al, or ORR et al, is with all of these but is with rituximab or at is an with an ORR in the study of et al, The ORR was at 40% in the randomised study et al, the that these patients were less Addition of rituximab the CR rate but are published on combination study of with et al, was but only included the active in the treatment of MCL, with response rates of et al, In to responses were in the and randomised trials et al, 2016). Addition of rituximab the ORR to in the only other published combination of and rituximab in patients an ORR of with CR et al, can the blood and is in CNS relapse et al, The is used the more it is (Rule et al, are a of combination therapies both at relapse and to have efficacy et al, 2016; et al, 2018). The have activity than rituximab in MCL, et al, 2013; et al, but the majority of the patients were to prior are difficult to The activity as a in MCL, with ORR 40% are with median and et al, The A phase trial et al, included patients with MCL and an ORR of and median of almost to results with et al, et al, 2008), et al, and et al, have been in MCL but the responses do not study has of ASCT with for first-line consolidation in MCL et al, 2005). This trial of and ASCT a for consolidation was shown (median months) no was There have been a of phase studies the role of consolidation more intensive induction regimens (Khouri et al, 1998; et al, 2003; et al, et al, et al, it is difficult to separate the of intensive induction from those of results are with and and rates of and from the recently reported MCL induction with or prior to and that of induction consolidation a of patients to an et al, 2016). of was an of have consolidation is intensive induction may results (Romaguera et al, given the excellent results intensive induction and this should be considered a standard of for suitable can be from intensive first-line therapy that a will be in the MCL trial ASCT a in Mantle such intensive first line patients will relapse (Geisler et al, 2012; et al, 2016). Prognostic factors of first line consolidation a or (Geisler et al, 2012), of an et al, 2016) and disease status at transplantation et al, et al, or was not an of in the Nordic MCL2 trial (Geisler et al, A of have been in an to first-line Addition of to toxicity but no in disease et al, The role of in therapy has been only in the of with the that patients in prior to ASCT may benefit from et al, 2016). There is however no regimen for ASCT in MCL. The of therapy and ASCT in the disease course has been in from both The Society for and and the for and studies that results of ASCT are when used in the first line (Vandenberghe et al, 2003; et al, with et al, A in the of and ASCT in MCL is the age of the patient of in patients more than years with ASCT to in patients of age et al, 2012). and ASCT for patients the age of in this patient group is The has been to be of in patients et al, but has not been in the of ASCT for MCL. the pattern of have been of has results and has no in therapy 2015; Rituximab therapy for a of years has recently been shown to both and first line ASCT et al, In this trial from the and were and for those rituximab and in the rituximab in the the of a stem cell by lymphoma by to and the of a for MCL however, to or with of is by of of including those in first-line and relapse settings and patients who have prior ASCT. studies with rates of at et al, et al, et al, et al, 2012; et al, disease in of patients and with this should be has been reported at between and with a of a in relapse even when is used et al, et al, 2012; et al, that may be able to MCL in a minority of patients et al, et al, et al, is to the of in MCL and the efficacy of et al, There is a of the role of in first-line The British Society of and trial of first line consolidation with a reported a rate of and a (Rule et al, 2016). The have reported that for patients an only or of prior therapy no prior relapse risk a was only with for those an ASCT. The benefit of a relapse rate however, by resulting in no in survival et al, can than ASCT in patients with high risk disease remains to be first line consolidation should only be considered the of a clinical on used in the relapse or in patients who have a prior ASCT is more et al, et al, et al, 2012; et al, 2013; et al, et al, As to be the results of when used in the disease course are not as good as when used et al, patients relapsing prior ASCT et al, and even those with disease at the of et al, 2013) may a that a minority of such patients may be and regimens may be considered but is no evidence of the of et al, the regimen should be according to age, and prior on an patient from studies the use of is with a relapse rate et al, et al, the overall of on survival remains et al, et al, 2013; et al, of for the majority of but this of transplantation in MCL et al, 2016). The of to the therapies also The BSH Haemato-oncology members at the of this guideline were and The to the BSH sounding and the BSH for in this The BSH the the of this have made a of to the BSH and Task may be on of the group will the group if new evidence that the strength of the made in this or it The will be and from the BSH website if it If new are made an will be published on the BSH website www.b-s-h.org.uk. the and in this guidance is to be and at the of to the the BSH the for the of this