The Management of Newly-Diagnosed Large B-cell Lymphoma: A British Society for Haematology Guideline

Recommendations

• Perform excision biopsy to provide the optimal material for diagnosis.1B
• Consider needle-core biopsy when a surgical approach is either impractical or entails excessive risk or delay.2B
• Diagnosis should be made in a reference haematopathology laboratory with access to a full range of phenotypic and molecular investigations.1A
• Discuss all diagnoses and treatment plans at a fully constituted haemato-oncology multidisciplinary team (MDT) meeting.1A
• All patients should have a full range of baseline blood tests to include serum lactate dehydrogenase (LDH) and full serology for hepatitis B (including core antibody), hepatitis C and HIV.1A
• Perform baseline PET-CT for all patients.1A
• Consider contrast-enhanced CT of neck, chest, abdomen and pelvis as an alternative if PET-CT is not practicable, or as an additional imaging modality in selected cases.2B
• Perform contrast-enhanced MRI of the brain (include spine if clinically indicated) and baseline CSF assessment (to include cytology and immunophenotyping) where there is clinical suspicion of CNS involvement.1B
• Consider contrast-enhanced MRI of the brain (include spine if clinically indicated) and baseline CSF assessment (to include cytology and immunophenotyping) for those considered at high risk of CNS involvement.2B
• Consider staging bone marrow biopsy only where discordant or alternative bone marrow pathology would influence clinical management.2B
• Perform a baseline ECG on all patients.1B
• Consider a baseline echocardiogram (or alternative imaging) to assess left ventricular function in older patients and those with relevant risk factors2B
• Record Eastern Cooperative Oncology Group (ECOG) performance status, International Prognostic Index (IPI) and CNS-IPI scores for all patients.1A
• Perform fluorescence in situ hybridization (FISH) for MYC rearrangements.1B
• If MYC is rearranged, evaluate for an immunoglobulin gene partner and perform FISH for BCL2 and BCL6 rearrangement.1B
• Determine COO in line with current classifications.2B
• Gene expression profiling and comprehensive genomics are not currently standard of care.
• Discuss and explain all diagnoses and treatment plans with the patient, and their family or carer if appropriate. Signpost to additional sources of support.1B
• Consider referral to relevant specialities (e.g. cardiology, health care of older people, endocrinology) for medical optimisation prior to and/or during treatment.2B
• Clinically assess osteoporosis risk in all patients.1B
• Consider vitamin D supplementation and bisphosphonate treatment according to risk profile. Consider seeking advice from an endocrinologist.2B
• Offer primary G-CSF prophylaxis to all patients receiving chemo-immunotherapy with curative intent.1B
• Consider primary prophylaxis against herpes simplex/zoster (e.g. aciclovir) and Pneumocystis jirovecii (e.g. co-trimoxazole).2B
• Consider well-designed clinical trials as an option for all patients2A
• Where more than one treatment approach is suitable, treatment decisions should be guided by the MDT and in accordance with patient preferences.2A
• Offer 4 cycles of R-CHOP plus 2 additional infusions of rituximab.1A
• Radiotherapy is not required if full dose intensity is delivered.1A
• Perform iPET2 after 2 initial cycles of R-CHOP
• If PET2 CMR (Deauville score (DS) 1-3), complete treatment with a further 2 cycles of R-CHOP.1A
• If PET2 not CMR (DS 4 or 5), deliver 4 further cycles of R-CHOP followed by radiotherapy consolidation (ISRT 30 Gy in 15 fractions).1B
• Consider combined modality therapy with 3-4 cycles of R-CHOP followed by radiotherapy consolidation (ISRT 30 Gy in 15 fractions).2B
• Consider 6 cycles of R-CHOP without radiotherapy where the risks of radiation are considered to be greater than 2-3 further cycles of R-CHOP.2B
• Offer 6 cycles of RCHP-polatuzumab vedotin or R-CHOP followed by end-of-treatment PET-CT.1B
• Consider radiotherapy consolidation according to baseline disease bulk and distribution, treatment response, and risks of radiation (ISRT 30 Gy in 15 fractions).2B
• Patients receiving less than full-dose intensity of chemo-immunotherapy (including those receiving RminiCHOP or less intensive rituximab-chemotherapy combinations).2B
• Patients with extra-nodal involvement (for specific primary extra-nodal sites refer to next section).2B
• Patients with bulky disease (≥7.5 cm diameter).2B
• For some patients with early-stage primary extra-nodal LBCL, the guidance for early-stage disease can be followed with exception of the primary disease locations listed below, which are generally treated with 6 cycles of chemo-immunotherapy and site-specific recommendations.2B
• Consider RCHP-polatuzumab vedotin for patients fit for full-dose chemotherapy with ECOG PS 0-2 and IPI 2-5.2B
• CNS prophylaxis is recommended in line with the current BSH good practice paper (GPP) on CNS prophylaxis.762B
• Offer 6 cycles of R-CHOP.1B
• Offer CNS prophylaxis guided by the current BSH GPP.1B
• Offer contralateral testicular radiotherapy following completion of systemic therapy.1B
• Consider consolidation radiotherapy to the involved breast to reduce risk of local recurrence in bulky or localised tumours.2C
• Consider CNS prophylaxis as per BSH GPP.2B
• Where H. pylori is detected, offer eradication therapy as per current guidance.1A
• Perform contrast-enhanced MRI of the brain (include spine if clinically indicated) and baseline CSF assessment (to include cytology and immunophenotyping) as baseline screening for CNS disease.1B
• Consider delaying the first rituximab infusion by ≥48 hours after chemotherapy administration to mitigate against the risk of a severe infusion reaction in cycle 1.2B
• Offer CNS prophylaxis as per BSH GPP for those with no evidence of CNS disease at baseline.1B
• Offer intensive CNS-directed secondary CNS lymphoma protocols for those with evidence of CNS disease at baseline.1B
• Offer consolidation radiotherapy to areas of previous bulky disease or localised, non-bulky tumours after completion of chemotherapy.1C
• Consider consolidation radiotherapy to reduce risk of local recurrence in bulky or localised tumours.2B
• Offer 6 cycles of RCHP-polatuzumab vedotin as first-line treatment for patients with de novo LBCL, fit for full dose chemotherapy, with an ECOG PS ≤2 and an IPI score of 2-5.1A
• R-CHOP can also be considered as an option for this group.2A
• Offer 6 cycles of R-CHOP as first-line treatment for patients with stage III/IV disease and an IPI score of 1.1A
• Consider a corticosteroid pre-phase and/or dose-attenuation (e.g. 50%) of cytotoxic agents for the first treatment cycle for patients with impaired PS and/or significant physiological compromise due to advanced stage disease.2B
• Consider more dose-intensive regimens such as R-CODOX-M/R-IVAC for younger patients (e.g. ≤50 years of age) with good performance status with IPI ≥3, particularly for those considered at high-risk of CNS relapse.2B
• Consider CNS prophylaxis for carefully selected high-risk patients in line with current BSH GPP.762B
• Consider radiotherapy consolidation for bulky disease on a patient-by-patient basis.2B
• RCHP-polatuzumab vedotin for patients with an IPI score of 2-5.2B
• 6 cycles of R-CHOP-21 or R-CHOP-14.2B
• For selected younger patients (where MYC is translocated to an Ig partner gene and co-exists with a BCL2 rearrangement), more intensive regimens such as DA-EPOCH-R or R-CODOX-M/R-IVAC may be considered.2B
• HDT-ASCT consolidation is not recommended as first-line therapy.1B
• Consider using a validated frailty index such as the EPI, if practicable, to help inform risks and benefits of therapy2B
• Offer a corticosteroid pre-phase (e.g. 1 mg/kg of oral prednisolone) in patients whose performance status is adversely affected by LBCL disease burden.1B
• Consider adding vincristine to corticosteroid pre-phase treatment (e.g. a single intravenous 1 mg dose).2B
• Offer R-miniCHOP (50% dosing of cyclophosphamide (400 mg/m2), doxorubicin (25 mg/m2) and vincristine (1 mg)) to patients ≥80 years.1A
• Consider dose-attenuation (e.g. 50% or 75%) of the chemotherapy components of R-CHOP in patients <80 years with clinically significant non-cardiac co-morbidities or impaired performance status.2B
• Offer a non-anthracycline-based regimen for patients with cardiac co-morbidities unsuitable for anthracyclines; options include RGCVP and RCEOP.1B
• Consider palliative approaches (low-intensity cytotoxic regimens, rituximab monotherapy, corticosteroids, palliative radiotherapy, or best supportive care alone) for very frail patients.2B
• Where interim imaging is planned, consider performing a PET-CT following 2 cycles of chemo-immunotherapy (iPET2) for an early assessment of response quality.2B
• A change of treatment should only be considered for those with no response or progressive disease on iPET2.1B
• Patients with early stage LBCL on a PET-adapted protocol should follow the appropriate management plan recommended at the outset.1A
• For patients with a complete metabolic response on iPET2, a contrast-enhanced CT scan is usually sufficient as end-of-treatment imaging.2B
• For patients without a complete metabolic response on iPET2 (or for patients who have not undergone an iPET2), an end-of-treatment PET-CT scan should be performed.1B
• End of treatment response should be assessed 3-6 weeks after the last dose of antibody.1A
• End-of-treatment imaging should be performed and reviewed in a timely manner, prior to consolidation radiotherapy or high-dose methotrexate, where planned.1B
• Consolidation radiotherapy should commence 6-8 weeks after completion of primary chemo-immunotherapy.1B
• After completion of radiotherapy consolidation, re-imaging should be performed at 12 weeks.1B
• Metabolic response should be ascertained using the Deauville criteria; DS 1-3 is regarded as CMR.1A
• The positive-predictive value of non-CMR is variable; biopsy is therefore strongly recommended prior to second line treatment.1A
• Offer biopsy of FDG-avid lesions wherever feasible.1A
• Offer a repeat PET-CT at an 8-12-week interval, where tissue biopsy is not possible and there is uncertainty regarding imaging findings.1B
• Consider ISRT to single FDG-avid lesions if considered suspicious of residual disease but where tissue biopsy is not feasible. Such decisions require careful patient counselling and close consultation with a radiation oncologist.2B