The management of newly diagnosed large B‐cell lymphoma: A British Society for Haematology Guideline

Abstract

This guideline was developed according to the British Society of Haematology (BSH) process, as set out on www.b-s-h.org/guidelines. 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 (see www.gradeworkinggroup.org). The manuscript was reviewed by the BSH Guidelines Committee Haemato-Oncology Taskforce, the Guidelines Committee and the Haemato-Oncology Sounding Board. It was on the member section of the BSH website for comment. The guideline has also been reviewed by patient representatives nominated by the UK charity Lymphoma Action (www.lymphoma-action.org.uk); this organisation does not necessarily approve or endorse the contents. This BSH guideline summarises the recommended initial investigation and first-line management of large B-cell lymphoma (LBCL). Primary extra-nodal LBCL is discussed in this guideline, with the exception of lymphoma involving the central nervous system, covered by separate BSH guideline publications.1, 2 Post-transplant lymphoproliferative disorders are also covered by a separate guideline.3 The investigation and management of primary mediastinal large B-cell lymphoma, mediastinal grey-zone lymphoma, primary cutaneous LBCL, primary effusion lymphoma, plasmablastic lymphoma and Burkitt lymphoma are also beyond the scope of this guideline. The management of relapsed LBCL is covered in a separate guideline. Large B-cell lymphomas (LBCLs) are a biologically heterogenous group of clinically aggressive malignancies arising from mature B lymphocytes. Current classification systems describe a number of LBCL subtypes based on morphological, molecular and clinical characteristics.4, 5 Where tumours do not meet the criteria for one of these specific disease entities, they are classified as diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS), or high-grade B-cell lymphoma, not otherwise specified (HGBCL, NOS). The vast majority of patients will receive systemic chemo-immunotherapy delivered with curative intent. The type of regimen, number of cycles and radiotherapy consolidation are influenced by a range of disease features and patient characteristics. Patients should be actively involved in all aspects of their care, and an understanding of their individual priorities should be established early to ensure person-centred care. Patients can also be signposted towards relevant charities for further information and support in an accessible format. Sufficient tissue sampling is essential for the accurate classification of LBCL, and excisional biopsy is recommended. However, while surgical excision is more likely to yield adequate material,6 if it is impractical, entails excessive risk or confers undue delay, then core biopsy is an acceptable alternative. There is generally no role for fine-needle aspiration and it can delay diagnostic tissue biopsy. Expert haematopathology review is essential, employing a full range of phenotypic and molecular investigations. Diagnostic material framed in a clinical context should be discussed at a multidisciplinary team meeting. Positron emission tomography (PET) using [18F] fluorodeoxyglucose (FDG) combined with low-dose computed tomography (CT) is the recommended imaging modality for staging of LBCL.7-9 In most cases, contrast-enhanced full-dose CT does not confer additional value.10, 11 PET-CT is more likely than bone marrow biopsy to detect marrow involvement with LBCL, and the presence of non-avid bone marrow disease does not confer a worse prognosis.12-16 Bone marrow biopsy may be considered for selected patients in whom a co-existing haematological condition is suspected (e.g. low-grade lymphoma or myelodysplasia), and where this would inform clinical management, but is otherwise unnecessary. Baseline tumour burden, as assessed by metabolic tumour volume on PET-CT is a promising biomarker.17, 18 Where suspected, central nervous system (CNS) involvement should be investigated by contrast-enhanced magnetic resonance imaging (MRI) of the brain and/or spinal cord together with cerebrospinal fluid (CSF) examination (cytology and flow cytometry).19 CNS investigations should also be considered for patients at high risk, informed by the CNS-International Prognostic Index (CNS-IPI)20 and the number (three or more) and location of extra-nodal sites of disease.21 Electrocardiography (ECG) should be performed on all patients prior to chemotherapy. Assessment of left ventricular function (echocardiography or multi-gated acquisition [MUGA] scan) should be considered for older patients, those with abnormalities on ECG and patients with a history of cardiovascular disease or risk factors. Patients with abnormal investigations may warrant clinical evaluation by a cardiologist. The significance of serum troponin concentration in this context is not established, and routine testing is not currently recommended. Serological testing for hepatitis B (to include core antibody), hepatitis C and human immunodeficiency virus (HIV) should be routinely performed prior to starting treatment. Patients with positive serology for hepatitis B should undergo viral DNA quantification and receive prophylactic antiviral therapy and hepatic B virus polymerase chain reaction (HBV PCR) monitoring, both during and after chemo-immunotherapy, as per current guidance.22 Referral to a hepatologist or infectious disease physician should be considered. Patients with positive serology for hepatitis C virus (HCV) require HCV RNA quantification and should be urgently referred to a hepatologist or infectious disease physician. Patients testing positive for HIV should be urgently referred for joint care from an HIV specialist at a centre of expertise.23 Those with well-controlled HIV (fully suppressed viral load and CD4 count ≥200 × 106/L) can be treated on the same protocols as patients who are HIV-negative. Reproductive counselling should be offered to all age-appropriate patients in whom potentially gonadotoxic therapy is planned. Sperm cryopreservation, ovarian preservation or oocyte harvest should be discussed where relevant. Patients who may be affected by the menopause during or after treatment should be signposted to their general practitioner for counselling, and the relevant investigations and hormonal replacement after completing treatment for lymphoma. Before starting therapy (including pre-phase treatment), a risk-based prophylaxis and monitoring plan for tumour lysis should be initiated.24 The International Prognostic Index (IPI) should be calculated for all patients.25 The National Comprehensive Cancer Network (NCCN)-IPI26 may allow better prognostic delineation of both high- and low-risk patients.27 The stage-modified IPI (smIPI) is discriminative in those with localised disease.28 Additional information should be incorporated into risk assessment including the presence of bulky disease (≥7.5 cm)29 and the presence of MYC and BCL2 (with or without BCL6) co-translocations. Both recently revised classifications4, 5 describe HGBCL with MYC and BCL2 rearrangements (with or without BCL6 rearrangement) as an aggressive lymphoma of GCB origin with distinct biology from other LBCLs. Data to support distinct biology in patients with MYC and BCL6 rearrangements are less compelling. In the WHO-HAEM5,4 dual MYC and BCL6 rearrangements are now classified either as a subtype of DLBCL, NOS or HGBL, NOS according to their cytomorphological features. The revised ICC5 has retained HGBCL-DH-BCL6 as a provisional entity to allow for continued study. MYC translocation to an immunoglobulin partner is most strongly associated with inferior overall survival.30 Other predictors of poor outcome, for example, TP53 mutations and ‘molecular high-grade’ gene expression signature,31, 32 are not yet routinely used in clinical prognostication. Gene expression profiling distinguishes molecular subtypes of LBCL according to the cell-of-origin (COO) model; a germinal centre B-cell (GCB) pattern is associated with more favourable outcomes than activated B-cell (ABC) disease.33-35 While surrogate COO delineation is possible with immunohistochemistry,36 and the distinction is retained in current consensus criteria,4, 5 it has limited utility in routine diagnostic practice outside clinical trials. More recently, comprehensive genomic approaches have identified a number of LBCL subgroups, but the clinical utility of this approach has not yet been established.37-39 Table 1 provides a summary of the investigations to be performed or considered at baseline. Investigations should be coordinated to minimise hospital visits and ensure the timely collation of results. Patients should be contacted early by a keyworker (e.g. a lymphoma clinical nurse specialist), who can help them navigate this process. Diagnostic biopsy Excisional biopsy preferred Core biopsy acceptable Molecular testing FISH for MYC translocation and Ig partner FISH for BCL2 and BCL6 translocations if MYC rearranged Baseline blood tests Full blood count Blood film Renal function and electrolytes Liver function Bone profile LDH Uric acid Immunoglobulins Virology (HBV (including core antibody), HCV, HIV) Blood grouping and antibody screen Imaging PET-CT Contrast-enhanced MRI brain and spine CSF flow cytometry Cardiac assessment ECG Echocardiogram MUGA Perform fluorescence in situ hybridisation (FISH) for MYC rearrangements (1B). Optimising all aspects of supportive care is important to reduce morbidity, particularly for elderly or frail patients. Patients often present with complex needs, and involvement of key members of the wider MDT (e.g. lymphoma clinical nurse specialists, pharmacists, cardio-respiratory specialists and healthcare of older people liaison teams) can prove invaluable. The risk of osteoporotic bone fractures is significant in the LBCL patient population.40 The 18-month cumulative incidence of frailty-related fractures was 11% in a UK study of LBCL patients ≥70 years.41 A predisposing history (osteoporosis, osteopenia, prior fracture and rheumatoid arthritis), bony involvement with lymphoma and receipt of pre-phase corticosteroids were independent risk factors. Baseline osteoporosis risk should be assessed (e.g. FRAX score). Patients receiving steroid therapy have been shown to benefit from vitamin D treatment in other contexts, so this may be considered.42 Bisphosphonate or similar therapies should be considered in patients at higher risk.43 Infection is a common cause of morbidity and mortality in the context of LBCL therapy.44, 45 Primary granulocyte colony-stimulating factor (G-CSF) prophylaxis and antimicrobial prophylaxis should be considered for all patients.46 Neutropenic prophylaxis with fluoroquinolone may be considered—informed by local microbiological guidance—for example, in patients with additional risk factors for infection. Treatment should be delivered in an appropriate clinical setting with adequate staffing, so that immediate complications can be managed according to applicable guidelines. Up to one-third of patients with LBCL present with early stage (I/II) disease, some of whom can undergo abbreviated systemic therapy (see below). Bulk has been conventionally defined as a maximal tumour diameter of ≥7.5 cm, although it is recognised that bulk is a continuum.29 A number of approaches to clinical management have evolved, although the heterogeneous populations included in the key trials introduces complexity to clinical decision-making; individualised multidisciplinary discussion is required. A minority of patients with early-stage LBCL will fulfil the eligibility criteria of the randomised phase 3 FLYER trial47: age 18–60 years with an IPI of 0 and non-bulky disease. Such patients should be offered abbreviated chemo-immunotherapy with four cycles of R-CHOP plus two additional as this was to cycles of R-CHOP with from the randomised phase 3 support an criteria were than for the FLYER bulky disease Patients were to treatment with cycles of or a where patients in metabolic after two cycles two further cycles of The approach was support for therapy is by the outcomes and overall after four cycles of R-CHOP in the of patients who were in on A of patients with early-stage disease also high of disease and with abbreviated R-CHOP However, the less favourable outcomes for patients, including those treated with combined modality that the approach for these patients is not yet Where a abbreviated chemo-immunotherapy is not combined modality treatment with abbreviated chemo-immunotherapy plus radiotherapy is generally from these and other have the risk of after first-line treatment for early-stage disease. outcomes to be similar patients treated with combined modality and chemo-immunotherapy involved therapy should be delivered according to A of patients with stage or disease risk including a high IPI or bulky disease. This group was recognised in a phase 3 randomised in all patients with a high stage-modified IPI cycles of an benefit from radiotherapy was not Additional on the benefit of radiotherapy after chemo-immunotherapy are and limited to factors be including of disease at of treatment and the and of radiotherapy The phase 3 with R-CHOP in more in the section of this included 11% of patients with stage disease and IPI The number of patients further of the early-stage However, their the is an for those with high In early-stage disease, and BCL2 or BCL6 rearrangement) and COO were not associated with or Perform after two initial cycles of R-CHOP radiotherapy to chemo-immunotherapy (including where an has been for patients with stage disease patients in the the of radiotherapy are considered to The management of primary extra-nodal LBCL is an of Patients with specific extra-nodal and primary extra-nodal disease with extra-nodal of are not in clinical trials of early-stage disease. of specific extra-nodal sites may have distinct extra-nodal subtypes are associated with inferior and treatment an stage LBCL specific are limited for a combined modality approach with abbreviated patients with primary extra-nodal LBCL have a However, those with IPI were for the and is an in this The role of CNS particularly in patients with primary LBCL, an of involvement by LBCL is associated with an inferior clinical with other subtypes of extra-nodal LBCL, in with a higher risk of CNS The management of this LBCL subtype is often based on the used in the phase study involved to cycles of four of and radiotherapy to the and in the patients were favourable with with and of and and cumulative incidence of CNS of The the same but incorporated four of and two cycles of of R-CHOP chemotherapy. from this study no CNS during the years of although extra-nodal were A of at of 5 years was Data to inform treatment of primary LBCL is but have high of both in the and and in the a CNS prophylaxis and consolidation radiotherapy are often considered. cycles of chemo-immunotherapy are Patients with LBCL are generally treated with cycles of modality treatment with to four cycles of by radiotherapy has shown However, is limited evidence for a role of radiotherapy after chemo-immunotherapy, and of the is often is generally for complications as or The risk of is hospital are not LBCL is and by B the of blood lymphomas more older patients and often the CNS of and is generally poor although patients with to more favourable outcomes has a significant outcomes in this disease although it may be associated with This may be during initial by after the of chemotherapy. to the high risk of CNS an and into an R-CHOP a of Primary cutaneous LBCL, type in older people with tumours on one or both but of at other sites and to sites is mutations are in to of outcomes were but from the study in the with of of systemic therapy is often limited in this older Primary bone LBCL is and bone disease is more as a of stage A of trials of DLBCL, identified of patients as primary bone disease, a of radiotherapy to involved In one radiotherapy was associated with outcomes in patients with early-stage extra-nodal LBCL, although the benefit is less in patients who are at of radiotherapy approaches for primary extra-nodal disease may of the affected The of the clinical volume for should be informed by the of disease, involved tissue volume and the for cycles of R-CHOP (1B). two cycles of R-CHOP delivered on a was a of care for the majority of patients with stage However, from the phase 3 randomised in the was incorporated into the in of an for the patients LBCL with of IPI of and for cycles of full-dose no in is of the two were similar although higher of and were in the from a benefit from patients with IPI or COO by However, the was not to evidence for specific and no have been It not possible to treatment in from the the of to recently significant in both for patients with a molecular high-grade gene expression profile and also for patients with an profile the COO was by is not yet in routine clinical Both treatment in cycles of chemo-immunotherapy, without two additional of a for this treatment approach that is now UK cycles of chemo-immunotherapy are also an in phase 3 trials of first-line treatment for Both treatment in included cycles of chemo-immunotherapy, without two additional of a for this treatment approach that is now UK cycles of chemo-immunotherapy are also as treatment in phase 3 trials of first-line treatment for randomised phase 3 trials have the with without and with While in and were with the higher of have limited of to R-CHOP not been in an of R-CHOP on a is not to a but a on with and may confer in for some the of benefit is as consolidation for patients in patients with disease from an phase 2 the outcomes for an risk and However, higher of morbidity and particularly in patients years or with should be The was with R-CHOP in the randomised phase 3 but no in outcomes was and the profile of was The investigated of for patients with a positive early after two cycles of There was no benefit for continued treatment with R-CHOP and was in the treatment evidence from the favourable outcomes for a group of patients who However, this to those who to on after two further R-CHOP these are not applicable to clinical practice the associated with of There is no approach towards consolidation radiotherapy (e.g. to sites of initial disease extra-nodal in the context of stage disease after A of patients with LBCL treated with to cycles of R-CHOP the role of in consolidation radiotherapy In this of patients and a of and of bulky disease not to outcomes in the the patients not in after initial chemo-immunotherapy, and their outcomes were similar to the The outcomes were in those not in who not receive It should be that of patients not in who not receive radiotherapy not a clinically important in (see also section on Treatment should be into and of the and the for therapies in the of disease cycles of as first-line treatment for patients with LBCL, for full-dose with an 2 and an IPI of There is no of care for patients with high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 Treatment patients or those with that the of full outcomes patients in and trials were considered if This has the patients systems have patient factors of but are and A assessment has been in patients patients years as or frail The elderly prognostic the IPI and levels to and high risk with of and However, the utility of systems to better inform beyond clinical assessment to be In the of patients with LBCL are the age of with a of The evidence the of R-CHOP is limited to trials or and the risk of in In patients evidence that full-dose of R-CHOP is important for However, in those outcomes full-dose R-CHOP and or large phase trials support the curative of and plus antibody Patients years treated with the a of In the phase the of the was mortality was with the of pre-phase and likely and a risk of clinically significant early A review the that should be of care in patients patients receiving R-CHOP for limited stage LBCL, is no evidence to the or number of treatment can be an important treatment in this age group where of may be less relevant. multidisciplinary care is essential for all patients with LBCL and is important for the complex of elderly or frail patients. and with patients, and members to their and early involvement of care are sites are for assessment and A approach that on of and may be more for frail or elderly patients. This may include radiotherapy or supportive care for selected patients. There is a for clinical including for the frail and elderly A number of have been developed for patients with significant history or left ventricular It should be recognised that and with to of morbidity and for A phase study of plus was in and were and was in patients with a of A of patients the of in of on and on a of A study on the elderly overall using or as with and a pre-phase (e.g. 1 of in patients is affected by LBCL disease (1B). from the randomised phase 3 that on is of favourable independent of have the prognostic significance of for IPI and COO In one of patients not in and who not receive further treatment not disease a of Where biopsy should be performed where is clinical or of lymphoma, into the clinical context and for treatment. The for is A number of have patients with at and The of patients with and from to range from to with a of in a study of patients receiving R-CHOP for the majority of are and the of in this group the of the the additional and The majority of LBCL the 2 years after However, do including in patients with early-stage The clinical to individual patients for routine beyond 2 years is not The and for should be informed by the of the disease, the treatment and be with the It is important to complications of LBCL including disease, bone early and may an for selected patients, although evidence limited to However, it is that patient to and support from of therapy is The should inform the of that is Where imaging is a PET-CT two cycles of chemo-immunotherapy for an early assessment of patients with of review imaging in an MDT to assess of disease and to were involved in the of the manuscript and in all the for The group is for the from and a patient on of lymphoma have been incorporated into the on supportive care and older patients. The BSH members at the of this guideline were and The the BSH and the BSH for their support in this guideline. support from the National for and and Comprehensive Cancer Imaging is by the and in with the and of and This was also by core from the for at and the The are those of the and not necessarily those of the the or the of and support from the National for and and have a of to the BSH and may be on The of are and and and support from of the group will inform the group if evidence that would the strength of the recommendations in this or it The will be reviewed by the Haemato-Oncology The will be and from the BSH current website if it recommendations are an will be on the BSH While the and information in this is to be and accurate at the of to the the BSH the for the of this guideline.

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