Guidelines for the management of diffuse large B‐cell lymphomaSridhar Chaganti, Tim Illidge, Sally F. Barrington et al.|British Journal of Haematology|2016 This guideline is aimed at providing healthcare professionals with clear guidance on the management of patients with diffuse large B-cell lymphoma (DLBCL). Disease confined to specific extranodal sites, such as primary central nervous system lymphoma, testicular lymphoma, primary mediastinal large B-cell lymphoma, DLBCL of leg type, etc., is beyond the scope of this guideline. It is not the intention of this guideline to provide treatment recommendations for all situations and clinicians are advised to make management decisions taking into account individual patient circumstances. The guideline group was selected to be representative of UK experts in the assessment and treatment of DLBCL. Recommendations are based on a systematic review of published English language literature up to January 2015. MEDLINE database was searched using the key words DLBCL, treatment, radiotherapy and transplant. References from relevant publications were also searched. Other published guidelines, including the US National Comprehensive Cancer Network (NCCN) and European Society for Medical Oncology guidelines, were also noted. The writing group produced a draft guideline. Review of the manuscript was performed by the British Committee for Standards in Haematology (BCSH) by the Haemato-oncology sounding board of the British Society for Haematology (BSH). This consists of 50 or more members of the BSH who have reviewed this Guidance and commented on its content and applicability in the UK setting. It has also been reviewed by a patient representative nominated by the Lymphoma Association, but the Association does not necessarily approve or endorse the contents. 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 are specified on the BCSH web site. (http://www.bcshguidances.com/BCSH_PROCESS/42_EVIDENCE_LEVELS_AND_GRADES_OF_RECOMMENDATION.html) and the GRADE working group website (http://www.gradeworkinggroup.org/index.htm). This is a new evidence-based guideline on behalf of the BCSH for the management of diffuse large B-cell non-Hodgkin lymphoma following a primary systematic review of the evidence by the writing group using the methodology described above. Diffuse large B-cell lymphoma is the most common non-Hodgkin lymphoma (NHL), accounting for 30–40% of all cases (Rodriguez-Abreu et al, 2007). Although most patients are cured with 6–8 cycles of R-CHOP (rituximab with cyclophosphamide, doxorubicin, vincristine and prednisolone) chemotherapy, about 10–15% have primary refractory disease and a further 20–30% relapse. The outlook for non-responders to R-CHOP is poor, though a significant minority can be cured by high dose chemotherapy (HDT) and haemopoietic stem cell transplantation. There is an urgent need to improve outcome for patients with DLBCL. Surgical excisional or incisional biopsy is strongly recommended to obtain adequate tumour tissue for diagnosis. Where this is not possible, core needle biopsies offer an alternative but frequently yield small and insufficient samples for diagnostic confirmation. Fine needle aspiration (FNA) is strongly discouraged. It is recommended that all diagnostic material be reviewed by an expert haematopathologist with clinicopathological correlation in the multidisciplinary team (MDT) setting. All patients should have baseline blood tests, including lactate dehydrogenase (LDH) and screening for human immunodeficiency virus (HIV), hepatitis B and hepatitis C. Left ventricular function should be assessed by echocardiogram or multigated acquisition scan in patients aged >65 years, and those with a cardiac history. Fertility-preserving treatments, such as sperm cryopreservation for male and referral to a fertility specialist in female patients, should be considered for eligible patients. A full contrast enhanced staging computerized tomography (CT) scan to include neck, chest, abdomen and pelvis should be performed in all cases. Magnetic resonance imaging (MRI)/CT imaging of the brain, orbits and sinuses will be required for patients with CNS or craniofacial disease. Diagnostic lumbar puncture for cerebrospinal fluid (CSF) analysis, including cytology and flow cytometry, is recommended for patients with suspected CNS involvement. Intrathecal methotrexate should be administered at the same time. A staging positron emission tomography (PET)/CT is strongly recommended as PET is more sensitive, especially for extranodal disease and improves staging accuracy and subsequent response assessment (Meignan et al, 2009; Barrington et al, 2010, 2014; Quarles van Ufford et al, 2010; Cheson et al, 2014).The role of a routine staging bone marrow biopsy (BMB) is under scrutiny as PET scanning demonstrates utility for identifying bone marrow involvement (BMI). This is usually seen as unifocal or multifocal uptake, with diffuse activity being less common. In a recent meta-analysis involving 654 patients with aggressive NHL, the pooled sensitivity and specificity for BMI was 89% and 100% respectively (Adams et al, 2014). In DLBCL, some studies suggest that PET is more sensitive for BMI than BMB (Berthet et al, 2013; Khan et al, 2013; Cerci et al, 2014), although low volume disease of <10–20% and discordant BMI with a low grade lymphoma may be missed (Paone et al, 2009). As low level (<10%) BMI with aggressive lymphoma is unlikely to affect prognosis (Campbell et al, 2006), the value of a staging BMB in DLBCL is currently a topic of hot debate. A BMB may nevertheless be required for patients where the presence of discordant BMI with low grade disease will affect management. Clinical prognostic markers predicting adverse outcome include advanced Ann Arbor stage, high International Prognostic Index (IPI) and bulk disease with a tumour diameter of >7·5 cm (The International Non-Hodgkin's Lymphoma Prognostic Factors Project 1993; Pfreundschuh et al, 2008a). The revised IPI (Sehn et al, 2007) confirms the prognostic significance of IPI in the R-CHOP era. The recently reported enhanced NCCN-IPI (Zhou et al, 2014), appears to better discriminate low and high risk groups. A high IPI also identifies patients at increased risk of CNS disease, which confers poor prognosis. Gene expression profiling (GEP) identifies distinct DLBCL subtypes, originating from either germinal centre (GCB) or activated B-cells (ABC) (Rosenwald et al, 2002). GEP of ABC-type predicted an inferior outcome in the CHOP era (Staudt, 2003). Although R-CHOP improves outcomes in both subtypes, DLBCL of ABC-type continues to have a worse prognosis (on univariate analysis) with a 40% 3-year progression-free survival (PFS) compared to 75% for the GCB-type (Lenz et al, 2008). Several immunohistochemistry (IHC) algorithms (Hans et al, 2004; Choi et al, 2009; Meyer et al, 2011) have attempted to reproduce the GEP classification with good correlation, but the resultant prognostic value has been inconsistent in patients treated with rituximab in addition to chemotherapy (Culpin et al, 2013). MYC rearrangements, found in 5–10% of DLBCL by fluorescent in-situ hybridization (FISH) (Obermann et al, 2009), confer a poor prognosis in R-CHOP treated patients (Savage et al, 2009; Barrans et al, 2010). Additionally, some patients have BCL2 and/or BCL6 rearrangement (double- or triple-hit lymphomas), also associated with a worse prognosis. Double-hit lymphomas (DHLs) tend to be clinically aggressive with a median survival of <12 months (Aukema et al, 2014; Li et al, 2014). Recent evidence suggests that the MYC partner gene is important; translocation to non-immunoglobulin (Ig) partner genes has little or no impact on survival (Pedersen et al, 2014). MYC and BCL2 protein overexpression as detected by IHC is much more common, occurring in 20–30% of DLBCL. This too confers an adverse prognosis with 5-year survival of <30–40% with R-CHOP (Green et al, 2012; Johnson et al, 2012; Hu et al, 2013). Unlike DHLs, which are usually of GCB-type, these tumours tend to be ABC-type. TP53 mutation and TP53 over expression are associated with decreased survival in both GCB and ABC tumours (Xu-Monette et al, 2012). The influence of other biological markers (such as BCL2, BCL6, Ki-67) on survival in the rituximab era is controversial. Patients with early stage DLBCL (stage IA or IIA disease) are treated variably with either full course chemotherapy or abbreviated chemotherapy with or without radiotherapy. In the pre-rituximab era, the Southwest Oncology Group study (SWOG 8736) showed that in localized aggressive NHL, combined modality treatment with 3 cycles of CHOP followed by involved field radiotherapy (IFRT) produced superior 5-year PFS (77% vs. 64%) and overall survival (OS) (82% vs. 72%) compared to 8 cycles of CHOP (Miller et al, 1998). However, this difference was lost with longer follow-up, suggesting that 3 cycles of chemotherapy may be inadequate for some patients with early stage disease. A British Columbia Cancer agency (BCCA) study showed 5-year OS of 95% with 3 cycles of CHOP plus IFRT in young patients with limited stage DLBCL and no adverse factors (Shenkier et al, 2002), further establishing this as an effective strategy. The Eastern Co-operative Oncology Group study (ECOG 1484) randomized complete responders after 8 cycles of CHOP to receive IFRT (30 Gy) or to observation alone and demonstrated an improvement in 6-year PFS with IFRT (73% vs. 56%) (Horning et al, 2004). The Groupe d'Etude des Lymphomes d'Adulte (GELA) performed a randomized study of elderly patients with limited stage disease and low risk IPI (GELA LNH 93-4). There was no benefit from adding radiotherapy to 4 courses of CHOP chemotherapy (Bonnet et al, 2007). In young patients (<60 years) with limited stage disease, the GELA LNH 93-1 study demonstrated a 5-year OS advantage for the intensive ACVBP/MIA (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone/methotrexate, ifosfamide, cytarabine) chemotherapy regimen over 3 cycles of CHOP and 40 Gy IFRT(Reyes et al, 2005). However, this study included patients with bulk disease (>10 cm) for whom 3 cycles of CHOP may be inadequate treatment. In a sub-group analysis, no survival difference was found between the two groups when comparing patients presenting with non-bulky disease. Furthermore, in both the above studies, there was a high loco-regional failure rate after radiotherapy (21%). The benefit of combined modality treatment has been reported in the rituximab era. The SWOG 0014 study reported a 4-year PFS of 88% and OS of 92% when rituximab was added to 3 cycles of CHOP plus IFRT (Persky et al, 2008). This represented an improvement over historical data from the pre-rituximab era (4-year PFS and OS of 78% and 88% respectively). The Mab-Thera International trial (MInT) trial, reported benefit in both OS and EFS when rituximab was added to CHOP-like chemotherapy in young (<60 years) patients with low risk IPI disease (Pfreundschuh et al, 2006). Most patients in this study had limited stage disease and IFRT was given to bulky (>7·5 cm) and extranodal disease. The optimal number of R-CHOP cycles for early stage disease is not clear. The German FLYER trial (NCT00278421) is currently comparing 4 vs. 6 cycles of R-CHOP for low IPI DLBCL patients. Whilst there are no published randomized trials of radiation therapy (RT) in the rituximab era to guide treatment decisions, a single centre retrospective analysis demonstrated an improvement in OS and PFS for patients receiving RT in complete remission (CR) after 6–8 cycles of R-CHOP chemotherapy. For patients with Stage I and II disease, the 5-year OS and PFS with RT were 92% and 82% whereas without RT they were 73% and 68% respectively (Phan et al, 2010). Recently, by international consensus, the radiation volume has been further reduced from IFRT to a new concept of Involved Site Radiation Treatment (ISRT) (Illidge et al, 2014). In conclusion, RT decreases local recurrence rates. For elderly patients and some younger patients with limited stage disease, 3–4 cycles of R-CHOP followed by ISRT may be preferable, especially for sites where RT is well tolerated, e.g. groin, axilla and neck. In contrast, a full course of 6–8 cycles of R-CHOP may be preferable where RT might in such as following treatment or increased risk following mediastinal radiotherapy in younger with the that the increased number of cycles of R-CHOP the risk of failure et al, 2009). Patients with stage or DLBCL or those with stage in the presence of B are treated as advanced stage disease. Several studies have the benefit of adding rituximab to including the GELA LNH et al, and et al, 2006). The German study (Pfreundschuh et al, demonstrated in outcome following the addition of rituximab in elderly the study showed the same for younger patients with low IPI disease (Pfreundschuh et al, 2006). The of dose in the rituximab era was by comparing with by the UK National Cancer et al, and the GELA et al, groups. studies showed no OS or PFS difference between and the treatment for advanced stage DLBCL. The GELA compared chemotherapy using 4 cycles of followed by with 8 courses of R-CHOP chemotherapy in young (<60 years) patients with low IPI disease et al, Whilst survival was better in the for the R-CHOP in this study were worse than be for this good risk group of patients. As the regimen was also associated with cyclophosphamide, with rituximab has also been reported to have significant especially in GCB-type DLBCL, in a Cancer and Group B II study et al, 2012). Patients with IPI DLBCL to have outcomes in the rituximab era with predicted 5-year survival of with A number of studies have attempted to improve outcomes for patients using either dose or stem cell in randomized trials comparing with and for high IPI disease were recently trials showed a PFS benefit for and but no at on OS and SWOG Lymphoma et al, 2012; et al, two trials to benefit for and et al, 2010; et al, 2012). and and be recommended a the German trial showed a 3-year survival of with R-CHOP plus Although not a randomized with this in a large 3 randomized study a significant improvement over R-CHOP in patients with high IPI disease. from a II UK study using the dose cyclophosphamide, doxorubicin, ifosfamide, cytarabine) regimen have also in this et al, Patients with have poor outcomes with R-CHOP chemotherapy. chemotherapy such as or are used for or lymphomas between DLBCL and in remission is also there is insufficient evidence to of these although retrospective studies suggest et al, 2014). Patients with DLBCL at risk of CNS disease should be considered for CNS This is in a BCSH guideline et al, IFRT has been used in trial for bulky and extranodal disease. analysis of the prognostic significance of tumour diameter in young patients with DLBCL was performed in the The analysis showed to be an adverse prognostic after treatment, with 3-year OS of for cm vs. for cm (Pfreundschuh et al, 2006). This study the study where patients with disease >7·5 cm were randomized to Gy IFRT or no further treatment. The study was by the Committee in to a significant advantage in PFS in patients receiving In an to the German trial, the value of adding Gy IFRT to sites of bulk (>7·5 cm) or extranodal disease was Patients receiving IFRT had superior PFS and OS et al, 2014). A large randomized trial comparing Gy with Gy showed no difference between the two et al, 2011) Gy the recommended dose for therapy in patients with disease using ISRT (Illidge et al, 2014). radiotherapy can be in patients a complete response to chemotherapy and the of Patients with chemotherapy refractory disease of radiotherapy on the individual A PET scan at the of treatment has a high value with a predicted PFS of However, the value is reported as et al, et al, et al, 2012). of a is advised to intensive chemotherapy an scan after 3 months of disease is The is recommended for response assessment et al, 2014; Cheson et al, 2014). PET scan R-CHOP chemotherapy is less of outcome et al, et al, et al, et al, than the of treatment with some studies no difference in outcomes to PET et al, et al, et al, 2012). treatment should not be on the of PET there is clear evidence of PET should be in to the and prognosis. biopsy and are strongly Factors predicting prognosis at include the IPI et al, et al, 2007) and of R-CHOP et al, 2010). For those for intensive followed by is The of is to disease and chemotherapy sensitivity to Although is not necessarily PET scan is of outcome following et al, et al, et al, 2009), with outcomes reported in those a complete remission et al, et al, The of include either or both of a or ifosfamide, and there is no superior regimen et al, 2010). should be based of and of impact on the to stem Whilst addition of rituximab to improves response in patients et al, 2004; et al, data are for those with with a regimen an is For patients who not to outcomes are poor with survival of et al, et al, 2010). Although clinicians a the of these patients is and they should be considered for trials of In the pre-rituximab era, survival benefit was demonstrated for patients with after a with chemotherapy et al, Other studies have reported that about a of patients a remission also survival with which is better than historical with chemotherapy alone et al, et al, et al, 2004). Although response to are in the rituximab era, outcomes following in patients et al, et al, 2012; et al, and recommendations are the The most used regimen for is and although other to yield outcomes et al, are to the of with the addition of localized radiation to sites of disease et al, 2010). of in and routine be recommended et al, 2013). benefit has been from using rituximab et al, 2012). there is insufficient evidence for et al, The role of radiotherapy or after is with some studies benefit for those with large volume et al, 2009; et al, no impact et al, et al, 2007). therapy to patients with PET activity following might be a in the of further The dose be but of up to Gy may be required for cases presenting with loco-regional or disease. clear recommendations can be on the of The prognosis of patients after is poor et al, a minority will to chemotherapy and may be considered for stem cell et al, et al, 2009; et al, 2010; van et al, et al, 2012; et al, 2012). to following and sensitivity to chemotherapy are the most prognostic is not recommended in those less than a a group of patients who should be considered for in to is there is no evidence that specific high risk benefit from survival outcomes are for and with following with et al, et al, 2010). Although can be recommended over the using a is a for younger patients years) with high risk or in those in whom is not to inadequate stem cell The between and reduced for is as studies are by criteria et al, et al, 2012; et al, 2013). In may be considered in patients of who have not had a with a reduced being for all Development of DLBCL is to of treatment with combined therapy and low cell et al, 2010). Patients with advanced stage disease and extranodal but survival is that seen in patients et al, 2014). Treatment is usually with either R-CHOP or such as with no randomized data to over the A recent retrospective UK study reported outcomes with R-CHOP et al, 2014). Although a randomized study reported increased rate of with the addition of rituximab to CHOP in patients with a of of blood et al, subsequent studies and a recent meta-analysis have the benefit of adding rituximab et al, et al, 2012). addition of rituximab to chemotherapy is recommended for all patients with and and Although there is some in is common to chemotherapy, where et al, 2014). For a of lymphomas to the British Association et al, 2014). Patients with disease should be treated to patients. with disease outcomes with to those of patients et al, 2009; et al, 2009; et al, 2010). The of R-CHOP with et al, 2012; et al, 2014; et al, 2014; et al, and et al, et al, 2012). in a minority of patients are treated with full dose especially following the of is to that of patients aged less than et al, to a assessment of for R-CHOP less and less effective There is no to an patient as is variably to those aged >65 or in studies, with patients being as such as the assessment et al, 2012; et al, or the et et al, may in identifying those patients who are for this two studies of R-CHOP in patients aged over reported 5-year OS of for all patients et al, and for and patients respectively et al, 2012). in both studies was low at As demonstrated by the of patients with a of may for R-CHOP (Pfreundschuh et al, 2004; 2010). in patients >65 with poor or significant the risk of and with R-CHOP in with European for and Treatment of Cancer guidelines, routine is recommended to improve treatment et al, 2003). have been in patients for The GELA group reported OS and PFS of and respectively using in patients aged years, with advanced stage disease and without significant or et al, The was other retrospective studies the of dose reduced R-CHOP in patients aged to et al, 2012; et al, 2013). may of vincristine or disease or risk et al, by an alternative data of prednisolone) et al, or cyclophosphamide, doxorubicin, et al, 2011) in patients for Patients who a following treatment should be followed up on a 3–4 for up to a trial, there is no role for routine and patients should be assessed The risk of beyond is et al, 2010; et al, 2010). It is to patients to primary at that stage with and The BCSH the the writing of this of the had of to All have a of to the BCSH and which may be on of the writing group will the writing group new evidence that the strength of the recommendations in this or The will be and from the BCSH website new recommendations are an will be published on the BCSH are required to in level of evidence or significant evidence recommendations a new of the guidance will be on the BCSH the and in this guidance is to be and at the of to the the BCSH the for the content of this the reviewed the literature and the draft of the and reviewed the literature and revised the The to Haematology for in the literature and for as a The to the BCSH Haemato-oncology and the BSH sounding the BCSH and the Lymphoma Association for in these