About 544,000 cases of NHL are diagnosed globally each year6

Incident cases from 2006 to 2016 increased by 45% globally1


~60% of NHL are aggressive subtypes and 40% are indolent subtypes8


There were an estimated 544,000 new cases of NHL and 260,000 deaths worldwide in 2020.6

  • An estimated 81,560 persons in the US will be diagnosed with NHL during 2021 (4.3% of all new cancer cases).43
  • An estimated 20,720 persons in the US will die from NHL during 2021 (3.4% of all cancer deaths).43

89.8% of NHL cases are diagnosed in persons older than 44 years.43

  • NHL is most frequently diagnosed among people aged 65 to 74 years.
  • The median age at diagnosis is 67 years.

Survival varies widely by cell type and stage of the disease.4

  • 73% of patients in the US will survive 5 years past diagnosis.43
  • 5-year survival by subtype:2
    • Diffuse large B–cell lymphoma (Aggressive) = ~64%
    • Follicular lymphoma (Indolent) = ~89%
    • Mantle cell lymphoma (Indolent & aggressive features) = ~62%

NHL are a heterogeneous group of neoplasms that originate in any of the lymphoid cells: B cells, T cells, or NK cells.4 There are over 60 subtypes identified by the World Health Organization, each categorized by cell of origin, histological appearance, immunophenotype, and genetic characteristics.5

B–cell lymphomas account for about 85% of NHL. Major NHL subtypes include8:

  • Diffuse large B-cell lymphoma (DLBCL): ~31%
  • Chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL): ~6%
  • Follicular lymphoma (FL): ~22%
  • Marginal zone lymphoma (MZL): ~8%
  • Mantle cell lymphoma (MCL): ~6% (US); 7% to 9% (Europe)7
  • Waldenstrom macroglobulinemia (WM): ~<1%

NHL subtypes are further characterized according to how the disease progresses.8

  • Indolent lymphomas
    • Slow-progressing
    • Few signs and symptoms when first diagnosed
    • About 40% of all NHL cases
    • FL is the most common subtype of indolent NHL
  • Aggressive lymphomas
    • Fast-progressing
    • Account for about 60% of all NHL cases
    • DLBCL is the most common subtype of aggressive NHL
  • MCL shares some characteristics of both indolent and aggressive NHLs

Subtypes of NHL have varied epidemiological and genetic risk factors.9 In most cases however, people diagnosed with NHL do not have any obvious risk factors, and many people who have risk factors for the disease never develop the malignancy.10


  • Increased young adult body-mass index (BMI), history of B cell-activating autoimmune diseases, and HCV seropositivity are associated with increased risk of developing DLBCL.9
  • BCL-2 protein overexpression is detected in approximately 30% of DLBCL cases; in approximately 90% of those cases, BCL-2 protein levels are very high.11,12
  • DLBCL may also be classified as double-hit lymphoma or double-expression lymphoma based on MYC and BCL2 gene characteristics25
    • Double-hit = MYC and BCL2 rearrangements
    • Double-expression = MYC and BCL-2 proteins are overexpressed, without rearrangements
    • Both are associated with a poor prognosis and worse outcomes
  • DLBCL may be further classified by its cell of origin.26
    • Germinal center B–cell (GCB)-type: ~50%
    • Activated B–cell (ABC)-type (poor prognosis): ~30%
    • The remaining 20% of DLBCL are unclassified


  • Family history of NHL and being overweight as a young adult are associated with increased risk of developing FL.9
  • Tumor grade, prognostic index and disease burden help guide therapeutic decision making and determine appropriate candidates for a watch-and-wait approach or active therapy.27
  • BCL-2 protein overexpression is detected in over 60% of FL cases.11
  • The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients.11


  • The etiology of MCL is likely multifactorial.9
  • MCL typically presents as an aggressive disease, with a median survival time of about 5 years.28,29
    • Clinical and biologic prognostic factors are used to stratify patients and assist in treatment decisions
  • MCL is characterized by the t(11,14) translocation that results in constitutive expression of cyclin D1.7,9
  • The BCL-2 pathway is commonly deregulated in MCL cases and the BCL2 gene is often amplified.14,15


  • Marginal zone lymphoma (MZL) is an indolent, mature B–cell neoplasm.30
  • MZL represents about 8% of NHL and there are three distinct types: extranodal MZL of mucosa-associated lymphoid tissue (MALT lymphoma), nodal MZL and splenic MZL.30
  • Up to ~80% of MZL have been shown to be BCL-2 positive.31


  • WM is rare indolent B–cell NHL characterized by the proliferation of B cells that produce an IgM monoclonal protein.32,33
  • Some patients do not need treatment at diagnosis but most require systemic treatment at some time.32
  • Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in WM.34
  • BCL-2 overexpression has been observed in WM patient samples, regardless of MYD88 or CXCR4 mutational status, suggesting an independent pathophysiologic mechanism.35

Presentation of NHL varies greatly depending on the type and aggressiveness of the lymphoma, as well as the area of involvement.16

An incisional or excisional lymph node biopsy is used to establish a pathologic diagnosis of NHL. Immunophenotypic analysis by flow cytometry and/or immunohistochemistry is essential for the differentiation of various subtypes of NHL.17

NHLs are staged using this general scheme; subtype-specific grading scales are used to more accurately identify the best course of treatment for disease.17

Immunochemotherapy (rituximab or obinutuzumab + chemotherapy) has emerged as the standard of care for most B–cell NHL.18


  • Immunochemotherapy is the standard of care for DLBCL.
  • Approximately one-third of patients eventually relapse or are initially refractory to these treatments.


  • Due to the vast heterogeneity, there is no uniform standard approach for treating FL and patient factors must be considered when deciding therapy.
  • While most patients have disseminated disease at diagnosis, they are frequently asymptomatic and have historically been observed without initial therapy ("watch-and-wait").21,22
  • For patients with symptomatic disease who are likely to be treated, immunochemotherapy is the standard of care.27
  • Despite the improved effectiveness of immunochemotherapy regimens, approximately 20% of patients with FL experience progression of disease within 2 years of first-line therapy.19,20
  • In particular, progression within 24 months of the start of 1L therapy (POD24) is a predictor of poor survival, with only 34–50% of patients alive at 5 years (vs ~90% in late-relapsed FL).20


  • For patients with asymptomatic newly diagnosed MCL and low tumor burden, close observation is acceptable, deferring therapy to the time of disease progression.7,23
  • In general, young and/or fit patients are considered for intensive immunochemotherapy strategies.7
  • Older MCL patients should be spared intensive strategies as the risk-to-benefit profile is not favorable.7,23
  • Although high overall response rates (ORRs) of 60% to 97% are observed after initial therapy, most often they are short lived, and most patients will eventually relapse.24


  • The standard of care for MZL can depend on the subtype; some MZLs can be associated with chronic immune stimulation due to infectious pathogens or inflammation. However, immunochemotherapy with rituximab is generally recommended for advanced-stage MZL.36,37,38


  • Although no clear standard of care for WM has emerged, BTK-inhibitor, alkylating agents, nucleoside analogues, anti-CD20 monoclonal antibodies and proteasome inhibitors can be used with high response rates.34,39,40,41

Multiple research groups have independently found that BCL-2 overexpression is associated with more advanced disease, poor prognostic features, and significantly lower survival rates.42

AbbVie is committed to helping address these challenges and is actively conducting research in this area to help address the unmet need.

Relevant Cancer Targets


Learn why the role BCL-2 plays in tumor survival makes it a rational target for therapeutic intervention.MORE>


Learn about CD19 and its expression on B cells signaling MORE>


Learn about CD3 on T cells and bispecific targeting of CD20 MORE>


Learn about MALT1 and NF-κB signaling. MORE>

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