Diffuse Large B-Cell Lymphoma (DLBCL)

Lead: Kevin Imrie
Date of last revision: June 1, 2020

Terms of use: These guidelines are a statement of consensus of the OCC Hematology site group regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult the Guidelines is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient's care or treatment. Use of this site and any information on it is at your own risk.

Diagnosis and pathologic classification:

Diffuse large B cell lymphoma is the most common histologic subtype of non-Hodgkin lymphoma accounting for ~25 per cent of cases. The 2017 WHO classification of Haematopoietic and lymphoid tumors a number of distinct diagnostic categories including [1]:

• T cell/histiocyte-rich large B cell lymphoma.
• Primary DLBCL of the mediastinum
• Intravascular large B cell lymphoma.
• Lymphomatoid granulomatosis
• Primary DLBCL of the central nervous system.
• Primary cutaneous DLBCL, leg type.
• DLBCL associated with chronic inflammation.
• EBV-positive DLBCL, not otherwise specified.
• Plasmablastic lymphoma.
• Primary effusion lymphoma.
• ALK-positive large B-cell lymphoma

In addition, the WHO provides overlap categories:

• “High grade B cell lymphoma with MYCand BCL2 and/or BCL6 rearrangements"
• "High grade B cell lymphoma, not otherwise specified."
• "B cell lymphoma, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma,"

This policy will not address each of these in details, as most of the less frequent entities will be discussed in MCC. See special considerations below for management of specific subtypes or presentations.

Baseline testing:

• Full history and physical including ECOG performance status [2] and frailty index [3] if appropriate. Testicular exam should be conducted in all males
• CBC, creatinine, uric acid, albumin, LDH, LFTs (Bilirubin, ALT, ALP)
• Hepatitis B surface antigen, Hepatitis B core antibody, Hepatitis C antibody and HIV serology
• CT head, neck, chest abdomen & pelvis
• FDG-PET/CT (may be omitted in patients being treated with palliative intent)
• Tb skin test
• strongyloides serology (and stool for ova+parasite) is recommended in patients who were born, resided, or traveled long-term (i.e. 6 months cumulative exposure to rural or beach areas, or contact with skin with sand/soil) in the following regions-southeast Asia, Oceania, Sub-Saharan Africa, South America, Caribbean, Mediterranean countries, Middle East, North Africa, Indian sub-continent, Asia
• MUGA scan or 2D echo (Age >60 or with cardiovascular risk factors)
• Bone marrow biopsy
• Lumbar Puncture (if CNS IPI 4+, encroachment of dura, HIV+, Testicular or high-grade)
• Pathology review if not reported at Sunnybrook or UHN
• FISH testing for MYC, BCL2 and BCL 6 will be considered in selected cases, including;
  • GCB like phenotype using Hans algorithm.
  • -High proliferation index.
  • -Double expression of MYC and BCL2
  • -BCL-U (spectrum of morphology between DLBCL and Burkitt lymphoma) and blastoid morphology.

Staging and prognostic factors:

Patients should be staged according to the revised staging system for primary nodal lymphomas [4] and the NCCN IPI [5]. The CNS IPI will be used to identify patients who are high risk and should be considered for CNS prophylaxis [6]. Cell of Origin (COO) is generally felt to be prognostic in DLBCL with patients with germinal centre B cell (GCB) profile being associated with better outcomes than those with activated B cell (ABC) or indeterminate phenotype in most studies. Gene expression profile is the gold standard for determining cell of origin but is not routinely clinically available. In its absence, immunohistochemistry (IHC) using the Hans algorithm is an imperfect surrogate. COO does not influence the choice of chemotherapy regimen but may influence the decision to test for dual/triple hit lymphoma, CNS prophylaxis (see below), and eligibility for some clinical trials [20].

Bulk definition: Mass >7cm in diameter

• ECOG performance status [2]
• Clinical Frailty Scale [3]

• NCCN IPI [5]

Risk Factors

• Age, y: <=40:0, 41-60: 1, 61-75:2, 76+:3
• LDH, normalized: <=1: 0, 1-3: 1, >3 2
• Ann arbor stage III-IV: 1
• Extranodal disease:1
• Performance status ³ 2: 1

5 yr OS:

Low (0-1): 96 per cent, L-I (2-3): 82 per cent, H-I (4-5): 64 per cent, High (6+): 33 per cent

Stage adjusted IPI IPI: (Age >60, Elevated LDH, ECOG >1): risk L (0-1), I 2, H (3-4) [7]

• CNS IPI [6]

Risk factors: Kidney and or adrenal involvement, Age >60, LDH >Normal, ECOG PS >1, Stage III/IV, extranodal involvement >1

Patients with >3 RF and non-GCB phenotype have >10% risk of CNS relapse and should be considered for CNS prophylaxis

Treatment:

First line:

Limited stage non bulky-low risk (0-1 FR on stage adjusted IPI) [7,8]:

CHOP+R x 4 followed by PET response assessment 4-6 weeks post last chemotherapy

• If in complete metabolic response: Observe
• If PET positive (Deauville 4/5): Radiation ³30 Gy

Limited stage bulky or high-risk (>1 RF on stage adjusted IPI)

CHOP+R x 6 followed by PET response assessment 4-6 weeks post last chemotherapy

• If in complete remission: Observe. Selected patients with bulk or with specific anatomic localizations may be considered for consolidative radiotherapy
• If PET positive (Deauville 4/5): Radiation ³30 Gy

Advanced stage [9]

• CHOP+Rx6. Selected patients with bulk or with specific anatomic localizations may be considered for consolidative radiotherapy. CCO will fund up to 8 cycles of Rituximab, however, it would be rare to plan to administer >6 cycles of CHOP+R

CNS Prophylaxis [10]:

• Patients who are at high risk according to the CNS IPI (>3 risk factors) and have a non-GCB phenotype should be considered for prophylaxis
• Administration of 3-4 cycles of high-dose MTX (3g/m2) on day 10 after R-CHOP cycles is the preferred option for fit patients under age 70
• 4 doses of IT MTX/AraC/hydrocortisone if not appropriate for HD-MTX

Supportive/Ancillary treatment:

• Allopurinol 300 mg daily x 7 days starting D-1 for cycle 1 only
• Filgastim/PegFilgastim primary prophylaxis if age >65, HIV positive, or felt to be at high risk (> 20%) of febrile neutropenia (open wounds, active infection, bone marrow infiltration by cancer, poor performance status, combined chemo-radiation). PegFilgastim will be administered in most cases, however, in cases where High-dose methotrexate is planned between CHOP-R filgastim would be the GCSF of choice due to shortened chemo-free interval and should be stopped 48 hours prior to chemotherapy
• Febrile neutropenia should be managed following Febrile neutropenia guideline 
• Fertility preservation should be offered to all patients if age appropriate 

Response assessment:

• CT between cycles 3 and 4 to ensure at least PR (Advanced stage)
• CT 4 weeks following the last cycle of chemotherapy. If residual abnormalities are identified on CT, a PET should be performed 4-6 weeks following last cycle of chemotherapy. Response will be assessed according to Lugano criteria (3). Patients failing to achieve a complete metabolic response should have biopsy to confirm refractory disease

Follow-up:

• Follow up visits every 3 months x 2 years, every 6 months x 3 years. Follow up will be transferred back to primary care physician between years 3 and 5
• At each visit: history and physical exam, CBC, LDH every 6 months; include TSH every 6 months if thyroid irradiated
• Counselling on physical and psychosocial issues, smoking cessation, age-appropriate cancer screening, immunizations
• Screening mammography and MRI starting at years 8-10 for women who received radiation to breast tissue

Second line:

• If eligible for high-dose therapy: GDP+R [11] and referral for Autologous stem cell transplant. Patients must have at least a PR to first-line therapy in order to be eligible for Rituximab funding.
• If not transplant eligible, consider clinical trial or alternately a palliative regimen such as cyclophosphamide/celebrex or VP 16/prednisone [12]

Beyond second line:

• Selected patients failing second line therapy will be considered for CAR-T cell therapy. The current CAR-T eligibility criteria and enrollment form can be found at Cancer Care Ontario's website. 
• If this option is not appropriate or available, patients will typically be considered for clinical trials or alternatively palliative treatment

Special considerations

Age: For patients over the age of 80 who are considered for curative intent treatment, consideration should be given to dose reducing chemotherapy using the Mini-CHOP regimen [13]

Double expressor/double hit lymphoma: All patients who express MYC along with BCL 2 or BCL 6 (double expressor) and those who have the MYC and BCL2 or 6 translocations (Double hit) should be presented for discussion at MCC. Patients with double hit lymphoma will be considered for DA-R-EPOCH (14).

Primary DLBCL of the Mediastinum: we recommend treatment with either CHOP-R for 6 cycles following by involved field irradiation or 6-8 cycles of DA-EPOCH-R [15]. DA-EPOCH-R is associated with greater toxicity but may obviate the need for mediastinal irradiation.

Testicular: Patients with testicular involvement will have a baseline MRI of brain and LP for staging. Treatment will be CHOP-R alternating with HD-MTX for 6 cycles of each followed by testicular irradiation [17].

Primary Cutaneous Large B cell lymphoma of skin, Leg type: Patients with Leg type DLBCL typically have a non-GCB profile and may have a poorer prognosis than other localized presentations and thus will typically treated as high risk localized with CHOP-R x 6 followed by PET scan and consideration of XRT as above [18].

Lymphomatoid Granulomatosis (LyG): Lymphomatoid Granulomatosis is a spectrum of disease. All patients with LyG should be discussed at MCC. Patients with asymptomatic low-grade disease can be managed conservatively, sometimes with observation. Those with symptomatic, extensive or progressive disease will be treated as DLBCL [19]

Other categories/rare presentations: Most patients with unusual variants of DLBCL should be discussed at MCC.

Useful tools

• Lymphoma staging 
• ECOG performance status (QxMD) [2]
• Clinical Frailty Scale: [3]
• NCCN-IPI calculator (QxMD)

• CNS IPI (QxMD)

Key references

1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, revised 4th edition, Swerdlow SH, Campo E, Harris NL, et al. (Eds), International Agency for Research on Cancer (IARC), Lyon 2017
2. Oken M et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649-655
3. Rockwood K et al. A global Clinical Measure of fitness and frailty in elderly people. CMAJ 2005; 173: 489-495
4. Bruce D. Cheson, Richard I. Fisher, Sally F. Barrington, Franco Cavalli, Lawrence H. Schwartz, Emanuele Zucca, and T. Andrew Lister Recommendations for Initial Evaluation, Staging, and Response Assessment of Hodgkin and Non-Hodgkin Lymphoma: The Lugano Classification. Journal of Clinical Oncology 2014 32:27, 3059-3067
5. Biccler J et al. Simplicity at the cost of predictive accuracy in diffuse large B-cell lymphoma: a critical assessment of the R-IPI, IPI, and NCCN-IPI. Cancer Med 2018; 7(1): 114-122
6. Klanova M et al. Integration of cell of origin into the clinical CNS International Prognostic Index improves CNS relapse prediction in DLBCL. Blood 2019; 133(9): 919-926
7. Norasetthada, L et al. Stage Adjusted International Prognostic Index (St-IPI) Is a Simple and Better Prognostic Model in Limited Stage Diffuse Large B-Cell Lymphoma (DLBCL): A Nationwide Multi-Institutional Registry in Thailand. Blood 2015 126 (23): 5030
8. Lamy T et al. R-CHOP 14 with or without radiotherapy in nonbulky limited-stage diffuse large B-cell lymphoma. Blood. 2018 Jan 11;131(2):174-181.
9. Coiffier B et al. CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma. N Engl J Med 2002; 346:235-242
10. Abramson JS et al. Intravenous methotrexate as central nervous system (CNS) prophylaxis is associated with a low risk of CNS recurrence in high-risk patients with diffuse large B-cell lymphoma. Cancer. 2010 Sep 15;116(18):4283-90
11. Moccia AA. Gemcitabine, dexamethasone, and cisplatin (GDP) is an effective and well-tolerated salvage therapy for relapsed/refractory diffuse large B-cell lymphoma and Hodgkin lymphoma. Leuk Lymphoma. 2017 Feb;58(2):324-332.
12. Danese MD et al. Second-line therapy in diffuse large B-cell lymphoma (DLBCL): treatment patterns and outcomes in older patients receiving outpatient chemotherapy. Leukemia & Lymphoma 2017; 58: 1094-1104
13. Eyre TA et al. Impact of intended and relative dose intensity of R‐CHOP in a large, consecutive cohort of elderly diffuse large B‐cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age. J Intern Med 2019.
14. Bartlett NL, Wilson WH, Jung SH, et al. Dose-Adjusted EPOCH-R compared with R- CHOP as frontline therapy for diffuse large b-cell lymphoma: clinical outcomes of the phase III intergroup trial Alliance/CALGB 50303. J Clin Oncol. 2019 Apr 2:JCO1801994.
15. Dunleavy K et al. Dose-adjusted EPOCH-rituximab therapy in primary mediastinal B-cell lymphoma. N Engl J Med. 2013 Apr;368(15):1408-16.
16. Ferreri AK et al. Whole-brain radiotherapy or autologous stem-cell transplantation as consolidation strategies after high-dose methotrexate-based chemoimmunotherapy in patients with primary CNS lymphoma: results of the second randomisation of the International Extranodal Lymphoma Study Group-32 phase 2 trial. Lancet Haematology 2017 Nov 4(11): 510-523
17. Vitolo U et al. First-line treatment for primary testicular diffuse large B-cell lymphoma with rituximab-CHOP, CNS prophylaxis, and contralateral testis irradiation: final results of an international phase II trial. J Clin Oncol. 2011;29(20):2766.
18. Senff NJ et al. European Organization for Research and Treatment of Cancer and International Society for Cutaneous Lymphoma consensus recommendations for the management of cutaneous B-cell lymphomas. Blood 2008; 112(5):1600
19. Pittaluga S, Wilson WH, Jaffe ES. Lymphomatoid granulomatosis. In: WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised Fourth Edition, Swerdlow SH, Campo E, Harris NL, Jaffe ES, Pileri SA, Stein H, Thiele J (Eds), IARC, Lyon 2017. p.312
20. Rutherford SC et al. DLBCL cell of origin: What role should it play in care today? Oncology 2018; 32(9): 445-9