Exploring dysfunctional pathways, mechanisms, and biomarkers in non-
Hodgkin lymphoma to discover new insights into the progression of the
INCIDENCE & MORTALITY
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
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
- Few signs and symptoms when first diagnosed
- About 40% of all NHL cases
- FL is the most common subtype of indolent NHL
- Aggressive lymphomas
- 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
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.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.
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- Swerdlow SH, Campo E, Pileri SA, et al. The 2016 revision of the World Health Organization classification of lymphoid neoplasms. Blood. 2016;127:2375-2390.
- Global Burden of Disease Cancer Collaboration; Sung H; Ferlay J, et al. Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA: Cancer J. Clin. 2021;71(3):209-249.
- Vose JM. Mantle cell lymphoma: 2017 update on diagnosis, risk-stratification, and clinical management. Am J Hematol. 2017;92(8):806-813.
- Leukemia & Lymphoma Society. NHL Subtypes. http://www.lls.org/lymphoma/non-hodgkin-lymphoma/diagnosis/nhl-subtypes. Accessed November 2020.
- Glass S, Phan A, Williams JN, Flowers CR, Koff JL. Integrating understanding of epidemiology and genomics in B-cell non-Hodgkin lymphoma as a pathway to novel management strategies. Discov Med. 2016;21(115):181-188.
- Mayo Foundation for Medical Education and Research. Diseases and Conditions: Non-Hodgkin's Lymphoma: Risk Factors. http://www.mayoclinic.org/diseases-conditions/non-hodgkins-lymphoma/basics/risk-factors/con-20027792. Accessed November 2020.
- Mahmoud HM, El-Sakhawy YN. Significance of Bcl-2 and Bcl-6 immunostaining in B-non Hodgkin's lymphoma. Hematol Rep. 2011;3(3):e26.
- Wang J, Zhou M, Xu J, Chen B, Ouyang J. Combination of BCL-2 and MYC protein expression improves high-risk stratification in diffuse large B-cell lymphoma. Onco Targets Ther. 2015;8:2645-2650.
- Scott DW, et al. Prognostic significance of diffuse large B-cell lymphoma cell of origin determined by digital gene expression in formalin-fixed paraffin-embedded tissue biopsies. J Clin Oncol. 2015;33(26):2848-2856.
- Perez-Galan P, Dreyling M, Wiestner A. Mantle cell lymphoma: biology, pathogenesis, and the molecular basis of treatment in the genomic era. Blood. 2003;101(6):2125-2131.
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- National Cancer Institute. Adult Non-Hodgkin Lymphoma Treatment (PDQ®)-Health Professional Version. https://www.cancer.gov/types/lymphoma/hp/adult-nhl-treatment-pdq. Accessed November 2020.
- Cheson B, Fisher RI, Barrington SF, et al. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014;32:3059-3067.
- Amin AD, Peters TL, Li L, et al. Diffuse large B-cell lymphoma: can genomics improve treatment options for a curable cancer? Cold Spring Harb Mol Case Stud. 2017;3(3):a001719.
- Press OW, et al. Phase III randomized intergroup trial of CHOP plus rituximab compared with CHOP chemotherapy plus 131iodine-tositumomab for previously untreated follicular non-Hodgkin lymphoma: SWOG S0016. J Clin Oncol. 2013;31(3):314-320.
- Casulo C, et al. Early relapse of follicular lymphoma after rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone defines patients at high risk for death: an analysis from the National LymphoCare Study. J Clin Oncol. 2015;33(23):2516-2522.
- Armitage JO, Longo DL. Is watch and wait still acceptable for patients with low-grade follicular lymphoma? Blood. 2016;127(23):2804-2808.
- Kahl B. Is there a role for "watch and wait" in follicular lymphoma in the rituximab era? Hematology Am Soc Hematol Educ Program. 2012;2012:433-438.
- Fakhri B, Kahl B. Current and emerging treatment options for mantle cell lymphoma. Ther Adv Hematol. 2017;8(8):223-234.
- Parrott M, Rule S, Kelleher M, Wilson J. A systematic review of treatments of relapsed/refractory mantle cell lymphoma. Clin Lymphoma Myeloma Leuk. 2017 Oct 13. [Epub ahead of print]
- Smith SM, et al. Aggressive B-cell lymphoma: the double-hit and double-expressor phenotypes. Clin Adv Hematol Oncol. 2017;15(1):40-42.
- Barton S, et al. Are we ready to stratify treatment for diffuse large B-cell lymphoma using molecular hallmarks? Oncologist. 2012;17(12):1562-73.
- Riedell PA, et al. How to Refine Treatment Choice in Follicular Lymphoma: From Low-Tumor Burden to High-Risk Follicular Lymphoma. Am J Hem/Onc. 2016;12(6):15-19.
- Hoster E, et al. A new prognostic index (MIPI) for patients with advanced-stage mantle cell lymphoma. Blood. 2008;111(2):558-65.
- Sarkozy C, et al. Complex karyotype in mantle cell lymphoma is a strong prognostic factor for the time to treatment and overall survival, independent of the MCL international prognostic index. Genes Chromosomes Cancer. 2014;53(1):106-16.
- Olszewski AJ, et al. Survival of patients with marginal zone lymphoma. Cancer. 2013 Feb 1;119(3):629-38.
- Lai R, et al. Frequency of bcl-2 expression in non-Hodgkin's lymphoma: a study of 778 cases with comparison of marginal zone lymphoma and monocytoid B-cell hyperplasia. Mod Pathol. 1998 Sep;11(9):864-869.
- Castillo JJ, et al. Overall survival and competing risks of death in patients with Waldenström macroglobulinaemia: an analysis of the Surveillance, Epidemiology and End Results database. Br J Haematol. 2015;169(1):81-9.
- Kyle RA, et al. Prognostic markers and criteria to initiate therapy in Waldenstrom's macroglobulinemia: consensus panel recommendations from the Second International Workshop on Waldenstrom's Macroglobulinemia. Semin Oncol. 2003 Apr;30(2):116-20.
- Treon SP, et al. Somatic mutations in MYD88 and CXCR4 are determinants of clinical presentation and overall survival in Waldenström macroglobulinemia. Blood. 2014;123(18):2791-2796.
- Castillo JJ, et al. Future therapeutic options for patients with Waldenström macroglobulinemia. Best Practice & Research Clinical Haematology 29 (2016) 206-215.
- Zucca E, et al. The spectrum of MALT lymphoma at different sites: biological and therapeutic relevance. Blood. 2016;127(17):2082-2092.
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- Rummel MJ, et al. Bendamustine plus rituximab versus CHOP plus rituximab as first-line treatment for patients with indolent and mantle-cell lymphomas: an open-label, multicentre, randomised, phase 3 non-inferiority trial. Lancet. 2013;381(9873):1203-10.
- Kastritis E, et al. Dexamethasone, rituximab, and cyclophosphamide as primary treatment of Waldenström macroglobulinemia: final analysis of a phase 2 study. Blood 2015. 126(11):1392-4.
- Dimopoulos MA, et al. Primary therapy of Waldenstrom macroglobulinemia (WM) with weekly bortezomib, low-dose dexamethasone, and rituximab (BDR): long-term results of a phase 2 study of the European Myeloma Network (EMN). Blood. 2013;122(19):3276-82.
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