Diffuse Large B-Cell Lymphoma (DLBCL)


The European Society for Medical Oncology (ESMO) and the National Comprehensive Cancer Network (NCCN) published comprehensive guidelines for the diagnosis, risk stratification, treatment, and monitoring of diffuse large B-cell lymphoma (DLBCL) in 2015.1,2 The NCCN published updates to its guidelines in 2019 and a patient version of the guidelines in 2022.3,4 

Diagnosis of DLBCL

A comprehensive physical examination must be conducted to assess the lymph nodes (including Waldeyer’s ring), examine the size of the liver and spleen, screen for a family history of lymphomas, and document the presence of B symptoms, such as fever, drenching night sweats, and the loss of more than 10% of body weight over 6 months.2,5 

It’s also important to analyze the patient’s ability to perform the activities of daily living independently. This information establishes a patient’s performance status using the Zubrod or Eastern Cooperative Oncology Group (ECOG) scale, on which scores range from 0 to 4.2,6

Lab Testing for DLBCL

Laboratory tests must include a complete blood cell (CBC) count, including platelet levels, and a comprehensive chemistry panel with particular attention to the lactate dehydrogenase (LDH) and uric acid concentrations.1,2 

Additional laboratory studies should include pregnancy testing for women of reproductive age, hepatitis B testing, and measurement of the β2-microglobulin concentration.2

Imaging for DLBCL

Imaging includes chest/abdominal/pelvic computed tomography (CT) with contrast and/or positron emission tomography (PET)-CT. Diagnostic accuracy is greater with PET-CT than with contrast-enhanced CT. Additional imaging to assess for spread to extranodal sites may include neck or head CT, magnetic resonance imaging (MRI), or lumbar puncture to determine the presence of lymphoma cells in the cerebrospinal fluid.1,2

Biopsy for DLBCL

Biopsy of the lymph nodes confirms a diagnosis of DLBCL. Surgical excision biopsy is preferable to needle-core or fine-needle aspiration biopsy, as it obtains adequate amounts of sample material for phenotypic and molecular analysis. Fine-needle aspiration biopsy should not be the primary or main method of DLBCL diagnosis; needle-core and endoscopic biopsy may be used in selected patients who cannot tolerate surgical biopsy.1,2 Biopsy must be repeated if the initial test results are inconclusive.2,7

Bone marrow biopsy (>1.6 cm ± aspirate) is required only in advanced cases of DLBCL and is not indicated if the PET result is negative.2 Focal bone marrow fluorodeoxyglucose (FDG)-PET determines cellular glucose uptake and may be used in place of bone marrow biopsy as detection is more accurate. One study reported that although both FDG-PET and bone marrow biopsy had a specificity of 100%, the sensitivity of FDG-PET was higher than that of bone marrow biopsy (94% vs 40%, respectively) to detect DLBCL infiltration into the bone marrow.1,8

Subtyping of DLBCL

Further analysis to determine DLBCL pathogenesis and subtype includes an immunohistochemistry (IHC) panel, flow cytometry, and cytogenetics or fluorescence in situ hybridization (FISH). 

The IHC panel evaluates CD20, CD3, CD5, CD10, CD45, BCL2, BCL6, MYC, Ki-67, IRF4/MUM1, CD30, CD138, cyclin D1, ALK, HHV8, EBER-ISH, and kappa/lambda. IHC and gene expression profiling are necessary to determine if a patient has activated B-cell (ABC) DLBCL or germinal center B-cell (GCB) DLBCL. ABC molecular subtypes of DLBCL typically have a worse prognosis than GCB subtypes.1,2,7,9 Gene expression profiling may also reveal a high level of expression of both MYC and BCL2 (double expressor lymphoma), which also carries a poor prognosis.1

Flow cytometry is used to analyze the cell surface markers CD45, CD3, CD5, CD19, CD10, CD20, and kappa/lambda.2,9

Cytogenetics or FISH assesses for chromosomal translocations to identify t(14;18), t(3;v), t(8;14), and t(8;v).2,9 An assessment to identify double- or triple-hit lymphomas, characterized by 2 or 3 chromosomal translocations, is also important for DLBCL prognosis.

Read more about DLBCL diagnosis

Risk Stratification of DLBCL

Both the NCCN and the ESMO recommend that the International Prognostic Index (IPI) score be calculated for risk stratification of patients. An age-adjusted version of the IPI (aa-IPI) is used for risk stratification in patients 60 years of age or younger.9

The IPI score is based on the following risk factors (1 point per factor)9:

  • Age >60 years
  • ECOG performance status score ≥2
  • Elevated serum LDH level
  • Stage III or IV disease
  • More than 1 extranodal site of disease

Patients are stratified according to the number of points on the 5-point IPI9:

  • Low risk (0-1 point)
  • Low-intermediate risk (2 points)
  • High-intermediate risk (3 points)
  • High risk (4-5 points)

The aa-IPI evaluates only LDH level, performance status, and disease stage on a 3-point scale9:

  • Low risk (0 points)
  • Low-intermediate risk (1 point)
  • High-intermediate risk (2 points)
  • High risk (3 points)

Treatment of DLBCL

Pre-Treatment Assessments

Before an anthracycline- or anthracenedione-based chemotherapy regimen is initiated, a multigated acquisition (MUGA) scan/echocardiogram must be performed to determine the patient’s cardiac ejection fraction. This can also identify any cardiotoxic effects of anthracycline treatment for DLBCL.2

The diameter of the largest affected lymph node must also be measured, as this is used to determine whether disease is nonbulky or bulky. Bulky lymphoma is defined as the presence of lymph node diameters larger than 7 cm in the coronal or transverse plane on CT.10

Immunochemotherapy for DLBCL

For patients with relatively localized stage I/II (nonbulky) DLBCL, first-line immunochemotherapy comprises 3 cycles of R-CHOP (Rituxan® with cyclophosphamide, hydroxydaunorubicin [sold as Lipodox® or Doxil®], Oncovin®, and prednisone) with or without subsequent involved-field radiation therapy (IFRT). If chemotherapy is not a viable option, patients may receive involved-site radiation therapy (ISRT).2,9

Read more about R-CHOP

For patients with stage II bulky DLBCL, the NCCN guidelines recommend 6 cycles of R-CHOP with or without subsequent radiation therapy.2,9

The ESMO guidelines also recommend the R-ACVBP regimen (Rituxan® with hydroxydaunorubicin [sold as Lipodox® or Doxil®], cyclophosphamide, vindesine, bleomycin, and prednisolone) to treat bulky DLBCL.1,9

For patients with advanced-stage DLBCL, the NCCN guidelines recommend 6 to 8 cycles (21-day cycle) of R-CHOP with radiation for bulky sites. Alternatively, clinicians may consider dose-adjusted etoposide, prednisone, Oncovin, cyclophosphamide, and hydroxydaunorubicin plus rituximab (DA-EPOCH-R).2,9

Read more about DLBCL treatment

Treatment for Refractory or Relapsed DLBCL

According to the NCCN, for refractory or relapsed DLBCL following high-dose chemotherapy, second-line treatments include the following, all of which may be given with or without rituximab2,9:

  • DHAP: Decadron® (dexamethasone), Cytosar-U® (cytarabine), and Platinol® (cisplatin)
  • ESHAP: methylprednisolone, etoposide, cytarabine, and cisplatin
  • GDP: Gemzar® (gemcitabine), dexamethasone, and cisplatin
  • GemOx: gemcitabine and Eloxatin (oxaliplatin)
  • ICE: Ifex® (ifosfamide), Paraplatin® (carboplatin), and etoposide
  • MINE: Novantrone® (mitoxantrone), ifosfamide, Mesnex® (mesna), and etoposide

For patients at increased risk for central nervous system involvement or relapse, the guidelines recommend 4 to 8 doses of intrathecal methotrexate and/or cytarabine or systemic methotrexate at 3 to 3.5 g/m2 for prophylaxis.2,9

Read more about DLBCL experimental therapies

Monitoring of DLBCL

PET should be performed to confirm complete remission of DLBCL. Following the Deauville criteria, end-of-treatment scan comparisons should be made with baseline scans in order to document DLBCL remission.11 Patients in complete remission should undergo clinical follow-up every 3 to 6 months for 5 years to monitor for relapse. These visits should include a CBC count, comprehensive metabolic panel, and LDH level measurement. After 5 years, these tests should be conducted annually or as clinically needed.9

For 2 years after the completion of treatment, CT-PET is recommended no more often than every 6 months and then only as clinically needed.9

Read more about DLBCL prognosis

References

  1. Tilly H, Gomes da Silva M, Vitolo U, et al. Diffuse large B-cell lymphoma (DLBCL): ESMO Clinical Practice Guidelines for diagnosis, treatment, and follow-up. Ann Oncol. 2015;26:v116-v125. doi:10.1093/annonc/mdv304
  2. NCCN clinical practice guidelines in oncology (NCCN guidelines®) non-Hodgkin’s lymphomas, version 2.2015. National Comprehensive Cancer Network. Published March 3, 2015. Accessed August 12, 2022. 
  3. Zelenetz AD, Gordon LI, Abramson JS, et al. NCCN guidelines insights: B-cell lymphomas, version 3.2019: featured updates to the NCCN guidelines. JNCCN. 2019;17(6):650-661. doi:10.6004/jnccn.2019.0029
  4. NCCN guidelines for patients: diffuse large B-cell lymphoma. National Comprehensive Cancer Network (NCCN). Published 2020. Accessed August 12, 2022. 
  5. NHL: signs and symptoms. Leukemia and Lymphoma Society. Accessed August 12, 2022. 
  6. West H (Jack), Jin JO. Performance status in patients with cancer. JAMA Oncology. 2015;1(7):998. doi:10.1001/jamaoncol.2015.3113
  7. Chaganti S, Illidge T, Barrington S, et al. Guidelines for the management of diffuse large B-cell lymphoma. Br J Haematol. 2016;174(1):43-56. doi:10.1111/bjh.14136
  8. Khan AB, Barrington SF, Mikhaeel NG et al. PET-CT staging of DLBCL accurately identifies and provides new insight into the clinical significance of bone marrow involvement. Blood. 2013;122: 61-67. doi:10.1182/blood-2012-12-473389
  9. Gandhi S. Diffuse large B-cell lymphoma (DLBCL) guidelines. Medscape. Updated May 6, 2021. Accessed August 12, 2022.
  10. Kumar A, Burger IA, Zhang Z, et al. Definition of bulky disease in early stage Hodgkin lymphoma in computed tomography era: prognostic significance of measurements in the coronal and transverse planes. Haematologica. 2016;101(10):1237-1243. doi:10.3324/haematol.2016.141846
  11. Barrington SF, Mikhaeel NG. PET scans for staging and restaging in diffuse large B-cell and follicular lymphomas. Curr Hematol Malig Rep. 2016;11:185-195. doi:10.1007/s11899-016-0318-1

Reviewed by Harshi Dhingra, MD, on 8/18/2022.