NHL are a heterogeneous group of neoplasms that originate in any of the lymphoid cells: B cells, T cells, or natural killer (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.⁴

B–cell lymphomas account for about 85% of NHL. Major NHL subtypes include⁷:

• 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.⁷

• 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.⁸ However, in most cases 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.⁹

DLBCL

• Increased young adult body-mass index (BMI), a history of B cell-activating autoimmune diseases, and Hepatitis C virus (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.^10.11
• DLBCL with translocations of MYC and BCL2 or BCL6 as detected by fluorescence in situ hybridization (FISH) or standard cytogenetics are known as “double-hit” lymphomas. If all three are rearranged, they are referred to as “triple-hit” lymphomas. The vast majority are germinal center B-cell-like lymphomas.²³
• DLBCL may be further classified by its cell of origin.²⁴
  • Germinal center B–cell (GCB)-type: ~50%
  • Activated B–cell (ABC)-type (poor prognosis): ~30%
  • The remaining 20% of DLBCL are unclassified
  • Gene expression profiling (GEP) can be used to divide DLBCL into GCB-type or ABC-type DLBCL, with a proportion remaining unclassifiable; attempts to divide by immunohistochemistry (IHC) have produced variable results resulting in the division of DLBCL into GCB-type and non-GCB type.⁴

FL

• Risk factors include family history of NHL, β2 microglobulin > upper limit of normal, bone marrow involvement, hemoglobin < 12g/dl, the diameter of the largest involved node > 6 cm, and age > 60 years.⁸
• Tumor grade, prognostic index, disease burden, GELF criteria help guide therapeutic decision making and determine appropriate candidates for a watch-and-wait approach or active therapy.²⁵
• BCL-2 protein overexpression is detected in 62.5% of FL cases.¹⁰
• The vast majority of patients with BCL-2 protein overexpression develop chemoresistance and experience higher relapse rates compared with BCL-2-negative patients.¹⁰
• BCL2/BCL6 mutation is associated with increased risk of transformed FL (tFL) and poor survival.¹⁰

CLL

• CLL is a slow-progressing cancer in which mature clonal B lymphocytes accumulate in the bone marrow, blood, and other lymphoid tissues.

• Vast genetic and epigenetic heterogeneity among patients and within individual patient samples has been observed; this likely contributes to the variability in clinical course among patients with CLL.²⁵

  • The most recurrent identified genomic lesions are deletions of chromosome 13q, 17p, and 11q; and trisomy of chromosome 12.²⁵

  • Unmutated IgVH is associated with more aggressive disease, poor prognosis, and decreased survival.²⁶

• The most relevant prognostic parameters are IgVH mutational status, serum β2-microglobulin, and the presence of del(17p) and/or TP53 mutations. Typically, high-risk CLL is defined in part by a genetic aberration of the TP53 gene (ie, del(17p) or TP53 mutation) or complex karyotype.²⁷

Presentation of NHL varies greatly depending on the type and aggressiveness of the lymphoma, and the area of involvement.¹⁴

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.¹⁵

* Whether stage II bulky disease is treated as limited or advanced disease may be determined by histology and a number of prognostic factors.

Immunochemotherapy (rituximab or obinutuzumab + chemotherapy) has emerged as the standard of care for most B–cell NHL.¹⁶

DLBCL¹⁶

• Immunochemotherapy is the standard of care for DLBCL in the front-line setting
• Although DLBCL is curable following front-line treatment, approximately one-third of patients eventually relapse or are initially refractory to these treatments.

FL^17,18,19

• Due to the heterogeneity of FL, 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").^19,20
• For patients with symptomatic disease who are likely to be treated, immunochemotherapy is the standard of care.²⁵
• Despite the improved effectiveness of immunochemotherapy regimens, FL is considered incurable and approximately 20% of patients with FL experience progression of disease within 2 years of first-line therapy.^17,18
• 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).¹⁸

• Numerous advances in the treatment of CLL have been made within the last few decades, including the introduction of novel classes of targeted small molecules such as BCL2 inhibitors or BTK inhibitors. 

• Randomized clinical trials have studied these therapeutics vs chemoimmunotherapy in both the first-line and relapsed/refractory setting.²⁸

• CLL is a chronic disease; therefore, most patients will relapse on or after treatment and require multiple lines of therapy, especially high-risk subgroups.

• The major treatment challenge has now shifted from having few therapeutic choices to how best to sequence and combine available agents.^28,29