Guideline sources The following summarized guidelines for the evaluation and management of diffuse large B-cell lymphoma (DLBCL) are prepared by our editorial team based on guidelines from the British Society for Haematology (BSH 2020; 2019), the European Society of Medical Oncology (ESMO 2018; 2016; 2015), and the British HIV Association (BHIVA 2014). 1 3 4 5 6 7 8 Calculator Calculator Calculat Eastern Cooperative Oncology G Karnofsky performance status s Modifie Guidelines 1. Classification and risk stratification Staging: use the Ann Arbor classification system for staging DLBCL. A Prognostic scores: As per ESMO 2018 guidelines: https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 1/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway Recognize that the International Prognostic Index parameters (age > 60 years, high LDH levels, poor performance status, advanced disease stage, and 1 extranodal site) are risk factors for early CNS relapse following first-line treatment of DLBCL, with a direct relationship between the number of unfavorable features and the CNS risk. B Recognize that the involvement of the testes, kidneys, adrenal glands, breast, bone marrow, and bone has also been reported to increase the risk of CNS disease. B As per ESMO 2015 guidelines, use the International Prognostic Index and age-adjusted International Prognostic Index scores for prognostic purposes. A 2. Diagnostic investigations History and physical examination: perform a physical examination and assess performance status and B symptoms in patients with DLBCL. B Imaging for staging: as per ESMO 2015 guidelines, obtain FDG-positron emission tomography/CT for staging DLBCL. B Show 2 more Laboratory evaluation: as per ESMO 2015 guidelines, obtain CBC, routine blood chemistry including LDH and uric acid, and screening tests for human immunodeficiency virus, HBV, and HCV. B Obtain protein electrophoresis. B Cardiac evaluation: assess cardiac function (LVEF) before initiating treatment. B 3. Diagnostic procedures Biopsy and histopathology: as per ESMO 2015 guidelines, perform surgical biopsy as the optimal method of diagnosis. B Show 4 more Ancillary testing: as per ESMO 2015 guidelines, obtain immunophenotypic investigations to confirm the morphological diagnosis of DLBCL. B Show 2 more Lumbar puncture: as per ESMO 2015 guidelines, consider performing a diagnostic lumbar puncture in high-risk patients. B 4. Medical management General principles: as per ESMO 2015 guidelines, stratify treatment strategies according to age, the International Prognostic Index score, and feasibility of dose-intensified approaches. Show 4 more Induction and consolidation therapy: as per ESMO 2015 guidelines, offer 6 cycles of combination chemotherapy with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) combined with 6 doses of rituximab every 21 days in young, low-risk patients (age-adjusted International Prognostic Index of 0) with non-bulky disease. Do not use https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 2/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway radiotherapy to initial non-bulky sites or consolidation in patients, whether treated with rituximab or not. A Show 4 more CNS prophylaxis: As per BSH 2020 guidelines, administer CNS prophylaxis in patients with any of the following: high (4-6) CNS-International Prognostic Index involvement of 3 extranodal sites irrespective of CNS-International Prognostic Index anatomical sites: testicular, renal/adrenal, intravascular. B Show 9 more As per ESMO 2018 guidelines: Obtain brain MRI and CSF analysis (by conventional cytology examination and flow cytometry) to assess patients with DLBCL considered as high risk for CNS relapse. B Avoid offering intrathecal chemotherapy in patients with DLBCL deemed at high risk for CNS relapse. Consider administering IV prophylaxis as an option in high-risk patients without evidence of CNS involvement. Offer a combination of anti-lymphoma drugs with good CNS bioavailability aimed at controlling both the CNS and systemic disease, preferably within a clinical trial, in patients with MRI and CSF evidence of CNS involvement at presentation. D As per ESMO 2016 guidelines, administer prophylactic therapy (such as intrathecal chemotherapy with methotrexate or IV systemic methotrexate) to reduce the risk of CNS relapse. B Show 2 more As per ESMO 2015 guidelines: Administer CNS prophylaxis in patients with high-intermediate-risk and high-risk International Prognostic Index, especially in patients with 1 extranodal site or elevated LDH or in patients with testicular, renal, or adrenal involvement. B Consider administering IV high-dose methotrexate for efficient disease control. C 5. Specific circumstances Patients with plasmablastic lymphoma: obtain immunohistochemistry tests (for CD38, CD20, PAX5, CD138, EBER, CD30, MUM-1, Kappa-lambda, HHV8, and ALK) as part of diagnostic assessment in human immunodeficiency virus-negative patients with suspected plasmablastic lymphoma. B Show 3 more Patients with HIV-associated DLBCL: As per ESMO 2015 guidelines, initiate the same treatment in patients with human immunodeficiency virus infection as in patients without human immunodeficiency virus in association with antiviral therapy. B As per BHIVA 2014 guidelines, administer chemotherapy regimens (such as CHOP or EPOCH) used in human immunodeficiency virus-negative patients for first-line treatment of diffuse large-B cell lymphoma in human immunodeficiency virus-positive patients. B https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 3/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway Show 3 more Patients with HBV infection: administer antiviral prophylaxis or obtain periodic HBV deoxyRNA monitoring and initiate antiviral treatment in patients previously exposed to HBV and experiencing reactivation of the virus during treatment. B Patients with central nervous system DLBCL, diagnosis: As per BSH 2019 guidelines, discuss suspected cases of cases primary CNS lymphoma with a primary CNS lymphoma specialist early in their pathway to minimize delays. B Show 5 more As per ESMO 2016 guidelines: Perform stereotactic biopsy as a minimally invasive technique to obtain a histopathological diagnosis. B Do not perform resection of primary CNS lymphoma. B Obtain testicular ultrasound in elderly male patients. B Patients with central nervous system DLBCL (baseline imaging): Obtain contrast-enhanced MRI (including diffusion sequences) as the imaging modality of choice before treatment and for response assessment. Review neuroaxis imaging (brain and entire spinal cord) by a specialist neuroradiologist. B Obtain cross-sectional imaging to exclude systemic disease in all patients: FDG-positron emission tomography-CT as the first choice A contrast-enhanced CT of the neck, chest, abdomen, and pelvis if positron emission tomography-CT is not possible B testicular ultrasound in male patients. B Patients with central nervous system DLBCL (ophthalmological assessment): obtain a thorough ophthalmological assessment, including slit lamp examination, in all patients to exclude intraocular involvement. B Patients with central nervous system DLBCL (cognitive assessment): Assess cognitive and quality of life outcomes in all patients with primary CNS lymphoma before and after treatment, with ongoing long-term monitoring. Assess cognitive domains of attention, processing speed, motor speed, executive function, and memory before and after treatment in all patients receiving treatment for primary CNS lymphoma. Patients with central nervous system DLBCL, induction chemotherapy: As per BSH 2019 guidelines, discuss all confirmed cases of primary CNS lymphoma at a lymphoma multidisciplinary team meeting. Initiate definitive treatment as soon as possible, ideally within 14 days of diagnosis, at an established center with multidisciplinary primary CNS lymphoma expertise. B Show 14 more As per ESMO 2016 guidelines, offer high-dose methotrexate-based regimens in combination with high-dose cytarabine for induction treatment if possible based on the patient's age, performance status, and organ function. A Show 2 more Patients with central nervous system DLBCL (consolidation therapy): recognize that whole- brain radiotherapy as consolidation after high-dose methotrexate-based chemotherapy is still https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 4/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway commonly applied in young patients and generally avoided in patients > 60 years because of the particularly high risk of neurotoxicity (including cognitive deterioration) in elderly patients. B Show 3 more Patients with central nervous system DLBCL (management of intraocular lymphoma): offer systemic high-dose methotrexate-based combination chemotherapy with rituximab for the treatment of primary intraocular lymphoma. Consider offering evidence-based primary CNS lymphoma induction protocols, such as the MATRix regimen, in fit patients. B Show 3 more Patients with central nervous system DLBCL (assessment of treatment response): obtain contrast-enhanced MRI (including diffusion sequences) as the imaging modality of choice for response assessment. Review neuroaxis imaging (brain and entire spinal cord) by a specialist neuroradiologist. B Show 5 more Patients with central nervous system DLBCL, salvage therapy: As per BSH 2019 guidelines, offer enrollment in a clinical trial, wherever possible. B Show 6 more As per ESMO 2016 guidelines: Insufficient evidence to recommend a standard protocol for salvage treatment. Consider offering high-dose chemotherapy followed by ASCT in fit patients. I Offer whole-brain radiotherapy as palliative treatment in patients with primary CNS lymphoma unable to tolerate or relapsing after high-dose, CNS-penetrating chemotherapy and not fit for further chemotherapy. B Patients with primary mediastinal DLBCL (mediastinal biopsy): perform a core or excisional biopsy to establish the histological diagnosis, reviewed by a specialist hematopathologist and discussed in a multidisciplinary team meeting to correlate clinical and pathological findings. A Patients with primary mediastinal DLBCL (bone marrow biopsy): Avoid performing bone marrow biopsy if a positron emission tomography-CT has been obtained. D Consider performing a bone marrow biopsy if it may influence patient risk management (CNS disease risk in patients presenting with extranodal disease or when a positron emission tomography-CT has not been obtained due to clinical urgency to initiate cytotoxic chemotherapy). C Patients with primary mediastinal DLBCL (baseline imaging): obtain baseline positron emission tomography-CT at diagnosis of patients with primary mediastinal DLBCL. A Patients with primary mediastinal DLBCL (fertility counseling): discuss regarding potential fertility preservation techniques before initiating chemotherapy, unless urgent lifesaving treatment is required. B Patients with primary mediastinal DLBCL (pregnant patients): manage pregnant patients presenting with primary mediastinal B-cell lymphoma in liaison with obstetricians and anesthesiologists spelcialized in high-risk pregnancies. B Patients with primary mediastinal DLBCL, induction therapy: https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 5/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway As per BSH 2019 guidelines, offer enrollment in a clinical trial, wherever possible. A Show 2 more As per ESMO 2016 guidelines, consider offering R-CHOP, R-VACOP-B, V-MACOP-B, R- CHOP14, or more intensive chemotherapy regimens, such as DA-EPOCH-R, as the current standard treatment in patients with primary mediastinal large B-cell lymphoma. B Patients with primary mediastinal DLBCL (consolidation therapy): offer consolidative mediastinal radiotherapy in responding patients treated with standard dose chemoimmunotherapy (R-CHOP/R-V/MACOP-B). B Show 3 more Patients with primary mediastinal DLBCL (assessment of treatment response): obtain positron emission tomography-CT at the end of combined modality treatment (2-3 months post-treatment) in patients receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone) and involved-site radiotherapy outside a clinical trial. B Show 5 more Patients with primary mediastinal DLBCL, salvage therapy: As per BSH 2019 guidelines, consider offering radiotherapy in patients omitted from initial therapy with localized relapse. B Show 2 more As per ESMO 2016 guidelines: Intensify therapy with high-dose chemotherapy/ASCT in young patients not achieving an adequate response (less than partial response) with an elevated FDG uptake at the post- chemoimmunotherapy positron emission tomography/CT, if residual disease is confirmed by biopsy when feasible. B Attempt reinduction with non-cross-resistant agents followed by consolidation with high- dose chemotherapy/ASCT as a salvage treatment strategy in patients with relapsed/resistant chemosensitive disease. B Patients with testicular DLBCL: perform orchiectomy for diagnostic and therapeutic purposes. B Show 5 more Patients with breast DLBCL: perform biopsy to establish the diagnosis of breast DLBCL. B Show 5 more Patients with bone DLBCL: offer R-CHOP chemotherapy with or without consolidation radiotherapy (30-40 Gy) as the standard approach in patients with any stage of DLBCL with bone involvement. B Show 4 more 6. Follow-up and surveillance Serial clinical assessment: elicit careful history and perform physical examination every 3 months for 1 year, every 6 months for 2 further years, and then once a year with attention to the development of secondary tumors or other long-term side-effects of chemotherapy. B https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 6/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway Serial laboratory assessment: obtain CBC at 3, 6, 12, and 24 months, then only as needed for evaluation of suspicious symptoms or clinical findings in patients suitable for further therapy. B Serial imaging assessment: as per ESMO 2015 guidelines, obtain FDG-positron emission tomography/CT post-treatment assessment in patients with DLBCL. A Show 2 more Repeat biopsy: as per ESMO 2015 guidelines, perform a biopsy in the presence of residual metabolically active tissue if salvage treatment is being considered. B Clinical findings Symptoms Past medical history Fatigue Ataxia-telangiectasia Fever Common variable immunodeficiency Night sweats EBV infection Shortness of breath Gastrointestinal bleeding Testicular lump HCV infection Weight loss Human immunodeficiency virus infection Head and neck exam Rheumatoid arthritis Neck mass SLE Severe combined immunodeficiency Lymphatic exam Sj gren's disease Cervical lymphadenopathy Superior vena cava syndrome Lymphadenopathy Wiskott-aldrich syndrome Imaging findings Abdominal exam Mediastinal enlargement Hepatomegaly Mediastinal lymphadenopathy Palpable abdominal mass Spinal cord compression Splenomegaly Lab findings serum LDH Studies 2020 TRIST In patients with hematologic malignancies requiring hematopoietic cell transplantation, restrictive strategy was noninferior to liberal strategy with respect to a health-related quality of life measured by Functional Assessment of Cancer Therapy-BMT score at day 100. Jason Tay et al. J Clin Oncol. 2020 May 1. https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 7/8 6/29/23, 10:17 PM Diffuse large B-cell lymphoma Pathway References 1. Christopher P Fox, Elizabeth H Phillips, Jeffery Smith et al. Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma. Br J Haematol. 2019 Feb;184 3 348 363. Open 2. Sridhar Chaganti, Tim Illidge, Sally Barrington et al. Guidelines for the management of diffuse large B- cell lymphoma. Br J Haematol. 2016 Jul;174 1 43 56. Open 3. H Tilly, M Gomes da Silva, U Vitolo et al. Diffuse large B-cell lymphoma DLBCL ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2015 Sep;26 Suppl 5:v116 25. Open 4. Kate Cwynarski, Maria A V Marzolini, Sally F Barrington et al. The management of primary mediastinal B-cell lymphoma: a British Society for Haematology Good Practice Paper. Br J Haematol. 2019 May;185 3 402 409. Open 5. Bower M, Palfreeman A, Alfa-Wali M et al. British HIV Association guidelines for HIV-associated malignancies 2014. HIV Med. 2014 Mar;15 Suppl 2 1 92. Open 6. U Vitolo, J F Seymour, M Martelli et al. Extranodal diffuse large B-cell lymphoma DLBCL and primary mediastinal B-cell lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v91-v102. Open 7. Pamela McKay, Matthew R Wilson, Sridhar Chaganti et al. The prevention of central nervous system relapse in diffuse large B-cell lymphoma: a British Society for Haematology good practice paper. Br J Haematol. 2020 Sep;190 5 708 714. Open 8. M Hutchings, M Ladetto, C Buske et al. ESMO Consensus Conference on malignant lymphoma: management of 'ultra-high-risk' patients. Ann Oncol. 2018 Aug 1;29 8 1687 1700. Open 9. Laurie H Sehn, Brian Berry, Mukesh Chhanabhai et al. The revised International Prognostic Index R IPI is a better predictor of outcome than the standard IPI for patients with diffuse large B-cell lymphoma treated with R CHOP. Blood. 2007 Mar 1;109 5 1857 61. Open 10. Abraham S Kanate, Ambuj Kumar, Peter Dreger et al. Maintenance Therapies for Hodgkin and Non- Hodgkin Lymphomas After Autologous Transplantation: A Consensus Project of ASBMT, CIBMTR, and the Lymphoma Working Party of EBMT. JAMA Oncol. 2019 May 1;5 5 715 722. Open 11. Steven H Kroft, Cordelia E Sever, Adam Bagg et al. Laboratory Workup of Lymphoma in Adults: Guideline From the American Society for Clinical Pathology and the College of American Pathologists. Arch Pathol Lab Med. 2021 Mar 1;145 3 269 290. Open 12. C Buske, M Hutchings, M Ladetto et al. ESMO Consensus Conference on malignant lymphoma: general perspectives and recommendations for the clinical management of the elderly patient with malignant lymphoma. Ann Oncol. 2018 Mar 1;29 3 544 562. Open https://web.pathway.md/diseases/recSlLC3Q5JGcLlHv 8/8