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

DLBCL

• 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

FL

• 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

MCL

• 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

MZL

• 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

• 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

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

DLBCL¹⁸

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

FL^19-21

• 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

MCL

• 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

MZL

• 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

WM

• 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.