The purpose of this research was to better understand and to identify a course of treatment for mantle-cell lymphoma. Lymphoma is a type of cancer that affects the Lymphatic system, a system that is heavily intertwined with the body’s immune system and works to fight infection. mantle-cell lymphoma specifically affects B-cells, a class of lymphocytes that produce antibodies to protect the body against foreign pathogens (1). This specific type of lymphoma can be classified by malignant B-lymphocytes, which occupy the mantle zone area of the lymph nodes (2). Symptoms are dependent on disease-progression and the specific region of the body affected. The most common symptoms, however, include swelling of certain lymph nodes, loss of appetite, nausea, vomiting, and abdominal pain (3). The disease is more common in men and typically affects people older in life, around 60-70 years old, however, specific causes of mantle-cell lymphoma remain unknown (4).

Two articles were used to identify treatment options for mantle-cell Lymphoma: Role of Bruton’s tyrosine kinase in B cells and malignancies and KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma. The prior article explains the role of Bruton’s Tyrosine Kinase (BTK) in causing mantle-cell lymphoma and other types of B-cell malignancies, and discusses the role of ibrutinib, a drug which inhibits this kinase. The latter article is a medical trial on KTE-X19 CAR-T cell therapy, a cutting-edge new treatment for relapsed and refractory mantle-cell lymphoma patients.

Kinases are a type of enzyme which catalyzes the phosphorylation of proteins. BTK is a kinase present downstream of the signal transduction pathway of the B-cell receptor (BCR), which is expressed on the surface of B-cells and acts to recognize and identify antigens (5). BTK is also involved with other signalling pathways in B-cells, such as chemokine receptor, Toll-like receptor, and Fc receptor signalling (6). Proper B-Cell signalling is essential to creating homeostasis within the cell and ensuring proper proliferation. A mutated BTK has been known to play a key-role in oncogenic signaling and is necessary for survival of malignant cells. The drug ibrutinib, an oral BTK inhibitor, has shown an objective clinical response in treatment for mantle-cell lymphoma. The drug works to covalently bond to the kinase domain and block kinase activity (7). Though ibrutinib and other BTK inhibitors are strong treatment options for relapsed or refractory mantle-cell lymphoma, a percentage of patients do not respond to the drugs or experience relapses.

KTE-X19 is a drug being tested for patients experiencing relapsed or refractory mantle-cell lymphoma after receiving BTK-inhibitor therapy. Typically, patients who do not respond to BTK-inhibitor therapy have a poor prognosis with a median overall survival rate of 6-10 months (8). KTE-X19 is a CAR-T cell therapy, meaning the patient’s immune system was altered by doctors to fight cancerous cells (9) In this specific case, special receptors, known as chimeric antigen receptors (CAR), were designed to bind to CD19, a protein specific to B-lymphocyte cells. These receptors were then added to T-cells to create a system where the body's own immune system attacks malignant cells.

A phase-2 trial of KTE-X19 occurred over three years in which 68 patients with relapsed or refractory mantle-cell lymphoma received treatment. All patients had previously received BTK inhibitor therapy. Results showed that of the 60 patients that completed the trial, 93% had an objective response, a decrease in tumor size, with 67% having a complete response, eradication of disease. All patients in the trial experienced at least one adverse event with 99% experiencing an adverse event grade 3 or higher. A grade 3 adverse event can be characterized by any condition severe or medically significant without being immediately life-threatening (10). Two patients died from adverse events related to treatment.

1. Indranil Mallick, "B-Cells in Your Immune System," Very Well Health, last modified May 4, 2020, accessed April 27, 2021, https://www.verywellhealth.com/b-cells-2252132.

2. Kaylie Schachter and Reem Karmali, "Mantle Cell Lymphoma," National Organization for Rare Disorders, accessed April 27, 2021, https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/.

3. Schachter and Karmali, "Mantle Cell," National Organization for Rare Disorders.https://rarediseases.org/rare-diseases/mantle-cell-lymphoma/.

4. WebMD, "Mantle Cell Lymphoma," WebMD, accessed April 27, 2021, https://www.webmd.com/cancer/lymphoma/mantle-cell-lymphoma#1.

5. Simar Pal Singh, Floris Dammeijer, and Rudi W. Hendriks, "Role of Bruton's Tyrosine Kinase in B Cells and Malignancies," Molecular Cancer 17, no. 57 (February 19, 2018): accessed April 27, 2021, https://doi.org/10.1186/s12943-018-0779-z

6. Singh, Dammeijer, and Hendriks, "Role of Bruton's.”

7. Singh, Dammeijer, and Hendriks, "Role of Bruton's.”

8. Michael Wang, "KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma," New England Journal of Medicine 382, no. 14 (December 11, 2020): [Page #], accessed April 27, 2021, https://doi.org/10.1056/NEJMoa1914347.

9. National Cancer Institute, "CAR T-cell Therapy," National Cancer Institute, accessed April 27, 2021, https://www.cancer.gov/publications/dictionaries/cancer-terms/def/car-t-cell-therapy.

10. Yuliya Yasinskaya, "Safety assessment in Clinical Trials and Beyond," FDA's Clinical Investigator Course, last modified November 13, 2012, accessed April 27, 2021, https://www.fda.gov/media/84954/download.

Ibrutinib, an oral BTK-inhibitor discussed in Article 1, has shown great success as a treatment for mantle-cell lymphoma; however, there is one rather outstanding issue with the drug: evolution. Ibrutinib is often prescribed as a life-long therapy (1). While the life-long prescription for many is a life-line, the long-term use of the drug can also backfire. As ibrutinib works by inhibiting certain kinases necessary for cancer life, certain mutations can make these kinases resistant to the drug’s effects. These resistant kinases will then be selected for, leading to continued proliferation of malignant B-lymphocytes. The ibrutinib example is a classic display of how evolution works. Ibrutinib is a factor which inhibits the growth of cancerous cells by inhibiting BTK. Mutations will form not in response to ibrutinib, but haphazardly. These mutations can then cause BTK to evade ibrutinib’s inhibitor effects and lead to the continued proliferation of cancerous cells. Kinases resistant to ibrutinib will then be selected for, causing colonies of cancerous cells to prosper. Overtime, the entire system evolves to become unresponsive to the ibrutinib drug. Because of the role natural selection plays, many patients actually experience relapses after being treated with ibrutinib for prolonged periods of time (2). These mutations and aggressive cancer cells often make further treatment difficult and lead to the slim prognosis many patients who relapse after taking BTK-inhibitors experience. As my research has shown, the median life expectancy following failed BTK-inhibitor treatment for a patient with mantle-cell lymphoma is 6-10 months (3). Luckily, KTE-X19 CAR T-cell therapy is a promising drug to treat such patients, as it utilizes the immune system to attack cancerous cells, a completely different approach that would not be altered by previous evolutionary benefits.

1. Simar Pal Singh, Floris Dammeijer, and Rudi W. Hendriks, "Role of Bruton's Tyrosine Kinase in B Cells and Malignancies," Molecular Cancer 17, no. 57 (February 19, 2018): [Page #], accessed April 27, 2021, https://doi.org/10.1186/s12943-018-0779-z.

2. Singh, Dammeijer, and Hendriks, "Role of Bruton's."

3. Michael Wang, "KTE-X19 CAR T-Cell Therapy in Relapsed or Refractory Mantle-Cell Lymphoma," New England Journal of Medicine 382, no. 14 (April 2, 2020): [Page #], accessed April 27, 2021, https://doi.org/10.1056/NEJMoa1914347.

mature lymphocytes with irregular nuclei

irregular lymphocyte cells