Lymphoma

Non-Hodgkin lymphomas represent a clinically and genetically heterogeneous group of lymphoproliferative disorders that arise in mature B lymphocytes (≈ 90% of cases), T lymphocytes 
(≈ 10%), or natural killer (NK) cells (< 1 %).1-3 Among the B-cell non-Hodgkin lymphomas, the more common forms include diffuse large B-cell lymphoma, follicular lymphoma, marginal zone lymphoma, and mantle cell lymphoma.1 Follicular lymphoma and marginal zone lymphoma are characterized by an indolent course of disease, whereas diffuse large B-cell lymphoma and mantle cell lymphoma exhibit a more aggressive clinical disease course.1,4-6 T-cell lymphoma subtypes include peripheral T-cell lymphoma, adult T-cell leukemia/lymphoma, and cutaneous T-cell lymphoma.7,8 NK cell lymphomas include extranodal NK/T-cell lymphoma, nasal type lymphoma, and aggressive NK-cell leukemia.2 The molecular pathogenesis of non-Hodgkin lymphoma is driven by a variety of chromosomal abnormalities and somatic mutations that alter the epigenetic landscape, gene expression, and cellular function of lymphocytes.4-9 Testing for the presence of specific proteins on the surface of B and T cells (ie, immunophenotyping) is important in the diagnosis of non-Hodgkin lymphoma.1,10

Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma is an aggressive B-cell non-Hodgkin lymphoma that includes 2 main subtypes: germinal center B-cell–like diffuse large B-cell lymphoma (GCB-DLBCL) and activated B-cell–like diffuse large B-cell lymphoma (ABC-DLBCL).5,11,12,14 Gene expression profiling distinguishes between the 2 main subtypes.5 In general, diffuse large B-cell lymphoma tumor cells are large and highly proliferative, which play a role in the characteristic aggressiveness of the disease.13,14 Diffuse large B-cell lymphoma presents with genetic lesions that are associated with the pathogenesis of the disease. Common genetic lesions found in GCB-DLBCL include translocations, deletions, amplifications, and mutations, like the t(14;18) chromosome translocation, which can lead to overexpression of genes like BCL2 that have been shown to be involved in suppression of apoptosis.5 Although similar types of genetic lesions are found in ABC-DLBCL, lesions specific to this subtype include constitutive activation of NFκB, which is required for survival and proliferation of ABC-DLBCL cells.5

Diffuse large B-cell lymphoma is the most common subtype of non-Hodgkin lymphoma, accounting for approximately 40% of non-Hodgkin lymphoma cases worldwide.13,15 Although recent treatment options have improved outcomes for patients with diffuse large B-cell lymphoma, there is still a need for new treatment approaches.1,16

Follicular Lymphoma

Follicular lymphoma is a subtype of B-cell non-Hodgkin lymphomas characterized by follicle structures within germinal center–derived B cells.17 Although many patients present with an advanced stage at diagnosis, follicular lymphoma is considered an indolent disease.19 Approximately 90% of follicular lymphoma cases have a t(14;18) translocation, resulting in deregulated expression of BCL2.1

During follicular lymphoma pathogenesis, infiltration of immune cells, such as T cells, dendritic cells, and reticular cells, promote immunosuppression via stimulation of B-cell receptors (BCRs), exhaustion of cytotoxic T cells, and T-cell evasion.19 In addition, expression of the inhibitory receptor programmed cell death 1 (PD-1) in follicular lymphoma cells is believed to affect the ability of T cells to mount appropriate antitumor responses.19

Follicular lymphoma accounts for 20% of all lymphomas.18 Follicular lymphoma is generally not curable by standard therapy and frequent relapses are common in patients demonstrating a need for improved treatment options.19

Marginal Zone Lymphoma

Marginal zone lymphomas are a group of B-cell malignancies originating from B lymphocytes and divided into 3 subtypes: extranodal (of mucosa-associated lymphoid tissue [MALT]), nodal, and splenic.1,20 Generally, marginal zone lymphomas are indolent and are associated with autoimmune disorders and bacterial infection.1,20 MALT lymphoma, the most common subtype, is marked by genetic translocations.1 One such translocation in gastric MALT results in the formation of a chimeric fusion gene API2-MALT1, which is associated with disease persistence or recurrence following treatment for H. pylori infection.1 Marginal zone lymphomas account for approximately 10% of all non-Hodgkin lymphomas.1 The rare nature of the disease has resulted in few randomized clinical trials.21

Mantle Cell Lymphoma

Mantle cell lymphoma is an aggressive, clinically heterogeneous form of B-cell lymphoma.1,22 The main oncogenic driver of mantle cell lymphoma is the chromosomal translocation t(11;14)(q13;q32), resulting in overexpression of cyclin D1, which may cause deregulation of the cell cycle.22 There are 2 subtypes of mantle cell lymphoma: classical mantle cell lymphoma, which typically involves lymph nodes and extranodal sites, and leukemic non-nodal mantle cell lymphoma, which commonly involves bone marrow, peripheral blood, and spleen.22 Mantle cell lymphoma accounts for 3% to 10% of non-Hodgkin lymphomas.23 Although mantle cell lymphoma typically responds to frontline chemotherapy, it is currently incurable with standard treatments.22

Peripheral T-Cell Lymphoma

Peripheral T-cell lymphoma, a heterogeneous group of T-cell lymphomas of post-thymic origin,2 is a relatively rare form of non-Hodgkin lymphoma, accounting for approximately 10% of non-Hodgkin lymphoma cases. Peripheral T-cell lymphoma-not otherwise specified is the most common subtype (26% of peripheral T-cell lymphomas) and most often involves nodal sites; however, many patients present with extranodal involvement, including in the liver, bone marrow, GI tract, and skin.2,24 Patients with relapsed or refractory peripheral T-cell lymphoma generally have a poor prognosis, representing an unmet medical need.25

Adult T-Cell Leukemia/Lymphoma

Adult T-cell leukemia/lymphoma is a subtype of peripheral T-cell lymphoma that is caused by the retrovirus human T-cell lymphotrophic virus type I (HTVL-1).2 Adult T-cell leukemia/lymphoma typically has a long period of latency and can have an aggressive disease course. There are 4 subtypes of adult T-cell leukemia/lymphoma: smoldering, chronic, acute, and lymphoma.2 Smoldering and chronic adult T-cell leukemia/lymphoma are considered indolent forms, whereas the acute and lymphoma subtypes are typically associated with rapid disease progression.2 Adult T-cell leukemia/lymphoma is endemic to Japan, the Caribbean, and parts of central Africa, and accounts for approximately 10% of cases of peripheral T-cell lymphoma or NK/T-cell lymphomas. Aggressive adult T-cell leukemia/lymphoma cells are often resistant to chemotherapy, which may potentially limit the activity of such agents in this disease.26

Cutaneous T-Cell Lymphoma

Cutaneous T-cell lymphomas are a heterogeneous group of extranodal non-Hodgkin lymphomas that mainly present on the skin.2,27 The incidence of cutaneous T-cell lymphoma was 9.6 per 1 million persons between 1998 and 2002.2 Mycosis fungoides (MF) is the most common subtype (50%-70% of cutaneous T-cell lymphomas), whereas Sezary syndrome (SS) accounts for only 1% to 3% of cases.2,28 Cutaneous T-cell lymphoma is associated with a complex genetic landscape leading to pathogenesis. Activating mutations in critical receptor signaling intermediates in conventional T cells have been identified as playing a role in cutaneous T-cell lymphoma pathogenesis.27 Although improved patient outcomes may be achieved with systemic chemotherapies, these responses are frequently short-lived, demonstrating an unmet need in the treatment of cutaneous T-cell lymphoma.27

The safety and efficacy of the agents and/or uses under investigation have not been established. There is no guarantee that the agents will receive health authority approval or become commercially available in any country for the uses being investigated

References

  1. NCCN Clinical Practice Guidelines in Oncology. B-Cell Lymphomas. V5.2017.
  2. NCCN Clinical Practice Guidelines in Oncology. T-Cell Lymphomas. V1.2018.
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  15. Union for International Cancer Control. Diffuse large B-cell lymphoma. http://www.who.int/selection_medicines/committees/expert/20/applications/DiffuseLargeBCellLymphoma.pdf?ua=1. Accessed October 20, 2017.
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  18. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Stat Fact Sheets: follicular lymphoma. https://seer.cancer.gov/seertools/hemelymph/51f6cf57e3e27c3994bd532a/. Accessed October 12, 2017.
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  23. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Stat Fact Sheets: mantle cell lymphoma. https://seer.cancer.gov/seertools/hemelymph/51f6cf57e3e27c3994bd5357/. Accessed October 10, 2017.
  24. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Stat Fact Sheets: peripheral T-cell lymphoma, NOS. https://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd52e8/. Accessed October 10, 2017.
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  28. National Cancer Institute. Surveillance, Epidemiology, and End Results Program. Stat Fact Sheets: primary cutaneous T-cell lymphoma. https://seer.cancer.gov/seertools/hemelymph/51f6cf56e3e27c3994bd52f7/. Updated. Accessed October 10, 2017.