MZL/FL - TG Therapeutics

FOLLICULAR LYMPHOMA AND MARGINAL ZONE LYMPHOMA (FL/MZL)

FL and MZL are two forms of indolent (slow growing) non-Hodgkin’s lymphoma (NHL)—the 8th leading cause of US cancer deaths in 2020.^1,2 Both FL and MZL are generally considered to be chronic and incurable diseases characterized by multiple recurrences and relapses.^3,4

FL is the most common form of indolent NHL and accounts for ~17.1% of all NHL cases.⁵
More than 13,000 new cases of FL are expected in the US in 2021, with ~12,500 patients with relapsed/refractory (R/R) FL on therapy each year.^6,7

MZL is the second most common form of indolent NHL and accounts for ~10.6% of all NHL cases.⁵ More than 8000 new cases of MZL are expected in the US in 2021, with ~6000 patients with R/R MZL on therapy each year.^6,7

Number of new cases and percent of total NHL cases

FL

13,200

MZL

8,200

FL AND MZL PATHOPHYSIOLOGY

FL and MZL are malignancies that arise from B cells.¹ B cells originate in the bone marrow and move into the lymphoid tissue, where they mature into effector cells, and ultimately memory B cells or plasma cells.⁸ Chromosomal translocations and/or mutations can arise during B-cell development within the lymphoid follicle, and these may contribute to the development of either FL or MZL.^8,9

Many patients with FL or MZL may be asymptomatic throughout their disease course and should be monitored continuously.¹

Immune dysfunction leads to a greater risk of lymphoma¹⁰

Mutations that occur during B-cell development are common, however most of these pre-cancerous cells are destroyed by the immune system.^8,11 However, a dysfunctional immune system may not be able to detect malignant (or neoplastic) cells, which can lead to the development of lymphoma.¹² Patients with weakened or dysfunctional immune systems (i.e. suffering from infections or autoimmune diseases) are at greater risk of developing lymphoma.¹⁰

Components within the B-cell receptor (BCR) signaling pathway are drivers of FL and MZL^13,14

Because FL and MZL arise from the uncontrolled proliferation of B cells, the BCR signaling pathway plays an important role in driving the proliferation and survival of lymphoma cells.¹⁴ Activation of the BCR results in the activation of downstream kinases, such as spleen tyrosine kinase (SYK), bruton tyrosine kinase (BTK), and phosphoinositide-3 kinase (PI3K, specifically PI3K-delta—an isoform that is highly expressed in B cells).¹⁴

SYK

SYK plays a role in lymphoma cell adhesion.¹⁵

BTK

BTK is important for cell proliferation, differentiation, and allows lymphoma cells to communicate with the immune microenvironment.^14,15

PI3K-delta

PI3K-delta promotes cell proliferation, survival, and migration of malignant B cells.¹⁵

Activation of the PI3K pathway is a common feature of FL and MZL that results in cell growth and survival.^16-18

PI3K proteins comprise a family of enzymes that can exist as 1 of 4 different isoforms (α, β, δ, γ) and regulate many signaling pathways involved in cell proliferation and survival.¹⁹ PI3Kδ is a key mediator of BCR signaling.¹⁹ Downstream of PI3Kδ are the proteins, AKT and mTOR, so this pathway is often referred to as the PI3K-AKT-mTOR pathway.¹⁹ Given the importance of the PI3K pathway in cancer, it is critical to understand the role of each PI3K isoform and the different cell types that are affected.

PI3Kα
PI3Kβ
PI3Kδ
PI3Kγ

Tissue/cell expression^20-24
- Broad distribution
- Broad distribution
- B cells
- T cells, macrophages neutrophils

Primary Function^20,23-27
- Plays a role in tumorigenesis
- Involved in insulin signaling and glucose metabolism
- Involved in platelet activation
- Plays a role in the development to thrombotic diseases
- Involved in the activation, proliferation, and survival of B cells as well as antibody production
- Involved in the innate immune response, suppress inflammation

Biological response when inhibited^19,20,22,25
- Blocks glucose uptake, resulting in hyperglycemia
- Defects in thrombosis, due to its effects on platelets
- Enhance anti-tumor immunity
- Activate T cells and macrophages to produce an inflammatory and/or autoimmune-like response

PI3Kα

Tissue/cell expression^20-24
Broad distribution

Primary function^20,23-27
Plays a role in tumorigenesis

Involved in insulin signaling and glucose metabolism

Biological response
when inhibited^19,20,22,25
Blocks glucose uptake, resulting in hyperglycemia

PI3Kβ

Tissue/cell expression^20-24
Broad distribution

Primary function^20,23-27
Involved in platelet activation

Plays a role in the development to thrombotic diseases

Biological response
when inhibited^19,20,22,25
Defects in thrombosis, due to its effects on platelets

PI3Kδ

Tissue/cell expression^20-24
B cells

Primary function^20,23-27
Involved in the activation, proliferation, and survival of B cells as well as antibody production

Biological response
when inhibited^19,20,22,25
Enhance anti-tumor immunity

PI3Kγ

Tissue/cell expression^20-24
T cells, macrophages neutrophils

Primary function^20,23-27
Involved in the innate immune response, suppress inflammation

Biological response
when inhibited^19,20,22,25
Activate T cells and macrophages to produce an inflammatory and/or autoimmune-like response

CLINICAL RESEARCH IN LYMPHOMA

We are researching new combinations and other targeted agents for B-cell malignancies.

TG Therapeutics is committed to researching
multiple targets in NHL.

Learn more about our clinical program

References: 1. Lymphoma Research Foundation. Understanding Non-Hodgkin Lymphoma: A guide for patients, survivors, and loved ones. https://lymphoma.org/wp-content/uploads/2021/04/LRF-NHL-Booklet_4.21.pdf. Accessed November 15, 2021. 2. National Cancer Institute. SEER Cancer Stat Facts: Common Cancer Sites. https://seer.cancer.gov/statfacts/html/common.html. Accessed January 14, 2021. 3. Rivas-Delgado A, et al. Brit J Haematol. 2019;184(5):753-759. 4. Denlinger NM, et al. Cancer Manag Res. 2018;10:615-624. 5. National Cancer Institute. SEER Cancer Statistics Review 2008-2017: Non-Hodgkin Lymphoma. Table 19.26. https://seer.cancer.gov/csr/1975_2017/results_single/sect_19_table.26_2pgs.pdf. Accessed October 14, 2021. 6. National Cancer Institute. SEER Cancer Stat Facts: Non-Hodgkin Lymphoma. https://seer.cancer.gov/statfacts/html/nhl.html. Accessed October 14, 2021. 7. TG Therapeutics. Data on file. 8. Küppers R. Nat Rev Cancer. 2005;5(4):251-262. 9. Huet S, et al. Nat Rev Cancer. 2018;18(4):224-239. 10. American Cancer Society. Non-Hodgkin Lymphoma Risk Factors. https://www.cancer.org/cancer/non-hodgkin-lymphoma/causes-risks-prevention/risk-factors.html. Accessed October 14, 2021. 11. Swann JB, Smyth MJ. J Clin Invest. 2007;117(5):1137-1146. 12. Kridel R, et al. J Clin Invest. 2012;122(10):3424-3431. 13. Dong S, et al. J Clin Invest. 2019;129(1):122-136. 14. Burger JA. N Engl J Med. 2020;383(5):460-473. 15. Burger JA, et al. Trends Immunol. 2013;34(12):592-601. 16. MacDonald D, et al. Curr Oncol. 2016;23(6):407-417. 17. Sindel A, et al. Blood. 2018;132 (1 suppl):4125. 18. Dienstmann R, et al. Mol Cancer Ther. 2014;13(5):1021-1031. 19. Fruman DA, et al. Cell Reports. 2017;170(4):605-635. 20. Kaneda MM, et al. Nature. 2016;539(7629): 437-442. 21. Ali AY, et al. Leukemia. 2018;32(9):1958-1969. 22. Ali K, et al. Nature. 2014;510(7505):407-411. 23. Esposito A, et al. JAMA Oncol. 2019;5(9):1347-1354. 24. Ortiz-Maldonado V, et al. Ther Adv Hematol. 2015;6(1):25-36. 25. Nylander S, et al. J Thromb Haemost. 2012;10(10):2127-2136. 26. Curigliano G, et al. Drug Saf. 2019;42(2):247-262. 27. Durand CA, et al. J Immunol. 2009;183(9):5673-5684.

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