INTRODUCTION:

Non-Hodgkin Lymphoma (NHL) are a heterogenous group of malignant lymphomas like B cell and T cell NK cells. Follicular lymphoma, Burkitt’s lymphoma, diffuse large B cell lymphoma, mantle cell lymphoma, marginal zone lymphoma and primary CNS lymphoma are the most prevalent adult B cell neoplasms. Adult T cell lymphoma and mycosis fungoides are the most prevalent mature T cell lymphomas.¹

Under normal circumstances, immune cells are the body's natural enemies of cancer cells, with no negative side effects4. Researching cancer therapies with few or no adverse effects, including triggering an immunomodulatory impact, is crucial. Therefore, medicines with such little side effects shouldn't destroy healthy cells, particularly immune cells.²In comparison to Hodgkin's lymphomas, non-Hodgkin lymphomas are a heterogeneous group of lymphoproliferative tumors that are far less predictable and have a much higher propensity to spread to extra nodal sites. The majority of NHL cases involve both nodal and extra nodal sites and account for about 25% of all NHL cases.³

Lymphoma affects the body’s lymph system (also known as the lymphatic system). The lymph system is part of the immune system, which helps fight infections and some other diseases. It also helps fluids move through the body. Lymphoma can also spread to the bone marrow and to other organs. The malignant lymphomas are a collection of neoplasms with variable degrees of malignancy that are derived from the histiocyte and lymphocyte building blocks of lymphoid tissue.

Non-Hodgkin lymphoma is not the same as Hodgkin lymphoma. Hodgkin lymphoma cells are also usually special cells called Reed-Sternberg cells. In non-Hodgkin lymphoma, cancer cells make up almost all of a lymph node, and there are no Reed-Sternberg cells in it. Less than 10% of people have any other NHL subtypes^.4 After prostate, breast, lung, colorectal, and bladder cancer, NHL is the sixth most prevalent cause of cancer-related death in the USA. After squamous cell carcinoma, oropharyngeal lymphomas are the second most prevalent malignancy in the oral region.⁵

Types of Hodgkin’s lymphoma:

It's critical for doctors to determine the precise type of lymphoma you have because treatment for NHL is based on the type. The affected lymphocyte type (B cells or T cells), the cell's level of maturity when it develops into a malignant state, and other variables all determine the type of lymphoma. In the body's initial line of defense, neutrophils are crucial because they phagocytize foreign cells and provide protection.⁶In cell culture, honey promotes the proliferation of B- and T-lymphocytes. An increased percentage of lymphocytes in rats fed honey for an extended period of time has also been seen in another study. The anti-inflammatory effect would be strengthened by the rise in lymphocyte numbers.

⁷

White blood cells called lymphocytes, which aid the body in fighting infections, make up the majority of the lymph system. The two primary categories of lymphocytes are:

1. B lymphocytes

2. T lymphocytes

1. B lymphocytes (B cells):

By producing antibodies, B cells generally aid the body's defenses against pathogens including viruses and bacteria. The antibodies bind to the pathogens, designating them for eradication by other immune system components.

2. Tlymphocytes (T cells):

These come in various varieties. Some T cells eliminate pathogens or aberrant cells from the body. Other T cells assist in enhancing or inhibiting the activity of other immune system cells. How ever, B-cell lymphomas are more frequent. Lymphoma can begin in any type of lymphocyte.

Classification:

Based on morphology and cell lineage, the WHO modified the Revised European-American Lymphoma (REAL) classification of NHL. Two divisions are recognized within the B-cell and T-cell categories: precursor neoplasms, which correspond to the earliest phases of differentiation, and more developed differentiated neoplasms.⁸The REAL classification is a thorough method that incorporates histologic, clinical, molecular, and genetic data. Patients are typically categorized as having Hodgkin's disease or lymphoid malignancies of the B-cell or T-cell kinds.

a. The WHO classification subtypes for NHL precursors are as follows:

1. Precursor B–lymphoblastic leukemia/lymphoma

2. Precursor T–lymphoblastic leukemia/lymphoma

b. The WHO classification subtypes for peripheral B-cell neoplasms are as follows:

· B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma

· B-cell prolymphocytic leukemia

· Lymphoplasmacytic lymphoma/ immunocyte

· Mantle cell lymphoma

· Follicular lymphoma

· Extra nodal marginal zone B-cell lymphoma of Mucosa-Associated Lymphatic Tissue (MALT) type

· Nodal marginal zone B-cell lymphoma (Monocytic B cells)

· Splenic marginal zone lymphoma (Villous lymphocytes)

· Hairy cell leukemia

· Plasmacytoma/plasma cell myeloma

· Diffuse large B-cell lymphoma (DLBCL)

· Burkitt lymphoma

c. The WHO classification subtypes for peripheral T-cell and NK-cell neoplasms are as follows:

· T-cell chronic lymphocytic leukemia/prolymphocytic leukemia

· T-cell granular lymphocytic leukemia

· Mycosis fungoides / Sezary syndrome

· Peripheral T-cell lymphoma, not otherwise characterized

· Hepatosplenic gamma/delta T-cell lymphoma

· Subcutaneous panniculitis-like T-cell lymphoma

· Angioimmunoblastic T-cell lymphoma

· Extra nodal T-/NK-cell lymphoma, nasal type

· Enteropathy-type intestinal T-cell lymphoma

· Adult T-cell lymphoma/leukemia (Human T-LymphotropicVirus [HTLV])

· Anaplastic large cell lymphoma, primary systemic type

· Anaplastic large cell lymphoma, primary cutaneous type

· Aggressive NK-cell leukemia

d. Non-Hodgkin’s lymphoma classification on the basis of location:

1) Oral cavity, Waldeyer's ring, and Pharynx:

· Small B-cell lymphoma

· Marginal mantle cell lymphoma

· Follicular lymphoma

· Extra nodal plasmacytoma

· Diffuse large B-cell lymphoma

· Extra nodal NK/T-cell lymphoma, Nasal type (Secondary extension).

2) Nasal cavity and per nasal sinuses:

· Small B cell lymphoma

· Lymphocytic lymphoma

· Follicular lymphoma

· Mantle cell lymphoma

· Marginal zone B-cell lymphoma

· Burkitt's lymphoma

· NK/T cell lymphoma, Nasal type.

3)Larynx and trachea:

· Small B-cell lymphoma

· Marginal zone B-cell lymphoma

· Extramedullary plasmacytoma.

· Diffuse large B-cell lymphoma.⁹

Epidemiology:

· Incidence:

The developed nations have higher incidence rates of NHL (with the exception of CLL and plasma cell malignancies), with the lowest rates in Eastern and South-Central Asia and the highest rates in the USA, Australia, and New Zealand. Around the year 2000, the incidence of NHL was reported to be 14 per 100,000 person-years (age standard; worldwide standard) in the United States and Canada, 10 per 100,000 in Denmark and Sweden, and 3 per 100,000 in South Central Asia¹⁰Malignant lymphomas (NHL and HL) ranked ninth among new cancer diagnoses among men and tenth among women in Sweden in 2003.¹¹NHL has recently risen to the sixth most common cancer diagnosed in the USA.¹²

· Time trends:

NHL incidence has dramatically increased globally over the past few decades, rising by roughly 4% yearly.^[13]Denmark experienced the biggest growth, where the rate doubled between 1970 and 1985¹⁴The rise in occurrence was seen in Scandinavia generally as early as the 1950s ¹⁵and in Connecticut, USA, even earlier.¹⁶In Sweden¹⁷, Denmark¹⁸, and other countries, the rise in incidence started to level down in the early 1990s. Since the 1970s, primary extra nodal lymphoma—especially those that affect the central nervous system—has risen more quickly than nodal types.¹⁹

The US National Cancer Institute convened an assembly in 1992 to assess NHL's historical trends. The increasing temporal trend was determined to be true at this meeting ²⁰ and it was also determined that known and suspected risk variables could not account for the observed increase over time.²¹ As shown in fig.1

Fig.1: Non-Hodgkin’s incidence in Sweden in 1960 to 2003 in males and females, age standardized to the Swedish population in the year 2000.

Pathophysiology:

Different stages of B cell development can lead to lymphomas:

The bone marrow serves as the primary lymphoid tissue where B cell development begins, and the spleen and lymph nodes serve as the secondary lymphoid tissue where B cell maturation occurs.

B cells interact with antigens through T cells in the secondary lymphoid tissue germinal centers, where they then go through affinity maturation to create immunoglobulins with a high affinity.

Lymphomagenesis is likely caused by somatically acquired genetic abnormalities (mostly translocations) of these pathways.

Only 15% of NHLs are T/NK cell-derived, while about 85% of NHLs are B-cell-derived.

The t (14;18) (q32; q21) translocation causes a greatly increased expression of BCL-2, an anti-apoptotic protein that prevents the healthy germinal center's default program of apoptotic cell death. This is a pathogenic characteristic.²²

Signs and symptoms:

Signs and symptoms of non-Hodgkin's lymphoma may include:

· Swollen lymph nodes in your neck, armpits or groin

· Abdominal pain or swelling

· Chest pain, coughing or trouble breathing

· Persistent fatigue

· Fever

· Night sweats

· Unexplained weight loss²³As shown in fig.2

Fig.2: Symptoms of Non-Hodgkins lymphoma

When they are close to the skin's surface, enlarged lymph nodes can make lumps under the skin feel palpable. Lumps that are typically itchy, red, or purple may also occur from lymphomas in the skin. Weakness, convulsions, cognitive difficulties, and changes in personality can all be brought on by brain lymphomas.²⁴Although endometriosis and non-Hodgkin lymphoma have been linked,²⁵ these relationships are tentative.²⁶

Etiology:

There are presumably various causes for the numerous different types of lymphoma. At least some of these potential reasons and connections with NHL include:

1. Agents of infection: Burkitt's lymphoma, follicular dendritic cell sarcoma, extra nodal NK-T-cell lymphoma, and diffuse large B-cell lymphoma are all linked to the Epstein-Barr virus.²⁷

2. Adult T-cell lymphoma is related to the human T-cell leukemia virus.

3. Gastric lymphoma is related to Helicobacter pylori.

4. Primary effusion lymphoma, multicentric Castleman disease, and HHV-8 are all linked.

5. Hepatitis C virus is linked to diffuse large B-cell lymphoma, lymphoplasmacytic lymphoma, and splenic marginal zone lymphoma.²⁸

6. Infected with HIV²⁹

7. Certain substances, including phenoxy herbicides, dioxin, and polychlorinated biphenyls diphenylhydantoin.^30-32

7. Radiation therapy and chemotherapy are examples of medical interventions.

8. Diseases of generic nature such as Klinefelter syndrome, chediak-higashi syndrome and ataxia-telangiectasia syndrome.

9. Autoimmune conditions such systemic lupus erythematosus, celiac disease, rheumatoid arthritis, and Sjogren syndrome.^33-34

10. Bone fractures and microfractures linked to bone marrow derived diffuse large B-cells lymphoma.

11. Silicone or hard metals implants connected to anaplastic large cell lymphoma.

Evaluation:

The National Comprehensive Cancer Network (NCCN) has provided the following recommendations for the diagnostic assessment of non-Hodgkin lymphomas. There is different test are used for diagnosing NHL. The doctor will first obtain a thorough medical history before determining whether the patient has NHL. Additionally, they will perform a physical examination, paying close attention to the lymph nodes, liver, and spleen. In addition to a physical examination, following tests may be used to diagnose and manage NHL.

· Biopsy:

A biopsy is performed by removing a small piece of tissue (referred to as a sample) so that cancer cells can be examined in it. The only reliable approach to determine if you have non-Hodgkin lymphoma is through a biopsy.

1. A bone marrow biopsy:

In a bone marrow biopsy, a needle is used to take a solid sample of bone marrow from the bone. In order to make the area painless before the treatment, local anesthetic is injected. A bone marrow biopsy is frequently performed in conjunction with a bone marrow aspiration, which takes a liquid sample of the bone marrow using a smaller needle. ³⁵As shown in fig.3

Fig.3: Bone marrow biopsy

2. Lymph node or tissue biopsy:

If one or more of the following lymph node features are present, a lymph node should be evaluated for biopsy: growth progression, considerable expansion, and durability for more than four to six weeks. The greatest diagnostic yields are typically found in lymph nodes larger than 2.25cm (i.e., a node with biperpendicular diameters of 1.5 x 1.5cm) or 2cm in a single diameter. For diagnosis, excisional lymph node biopsy is the gold standard. Avoid using fine needles to release the lymph node. Excisional biopsy of an intact node provides enough tissue for hematopathologists to evaluate and classify the node's histology, immunology, and molecular biology.^36-37

· Image-based tests:

Imaging tests may be advised by your doctor to look for lymphoma cells elsewhere in your body. CT, MRI, and positron emission tomography (PET) are a few possible tests.³⁸

· Tests on blood and urine:

An infection or other disease may be ruled out with the use of blood and urine testing.

· Health checkup or physical exam:

Your doctor examines your spleen, liver, and lymph nodes in your neck, underarm, and groin for swelling.

Treatments:

§ Radiation therapy:

High-energy radiation, such as x-rays or other forms of radiation, is used in radiation therapy to either kill or stop the growth of cancer cells. Radiation is directed at the part of the body with cancer using an apparatus outside the body in external radiation therapy. Prior to a stem cell transplant, complete body radiation therapy may be administered. An external form of high-energy radiation therapy called a proton beam uses streams of protons, which are small particles with a positive charge, to destroy tumor cells. Healthy tissue close to a tumor, like the heart or breast, may suffer less radiation damage as a result of this sort of treatment. Natural or therapeutic radiation is innocuous, but when it enters a cell and targets its constituent parts—most notably the DNA, which can lead to mutation, cell death, and cancer—damage begins at the cellular level.³⁹

§ Chemotherapy

Chemotherapy is a form of cancer treatment that employs medications to kill cancer cells or prevent them from proliferating in order to stop the growth of cancer cells. Chemotherapy medications can reach cancer cells throughout the body whether administered orally or by injection into a vein or muscle (systemic chemotherapy). Regional chemotherapy is used when chemotherapy is administered directly into a body cavity, such as the belly, an organ, or the cerebrospinal fluid (intrathecal chemotherapy). Treatment utilizing two or more anticancer medications is known as combination chemotherapy. To reduce inflammation and the body's immunological reaction, steroids may be added. Intrathecal chemotherapy may also be used in treatment of non-Hodgkin’s lymphoma. Anticancer drugs are injected into the intrathecal space, which is the space that holds the cerebrospinal fluid (CSF, As shown fig.4 in blue)

Fig.4: Primary CNS lymphoma treatment

There are two ways to accomplish this. An Ommaya reservoir, a dome-shaped container positioned beneath the scalp during surgery that stores the medications while they flow down a tiny tube into the brain, is one method, as is depicted in the top portion of the picture. The alternative method, illustrated in the lower portion of the picture, involves numbing a small section of the lower back before injecting the medication directly into the CSF in the lower part of the spinal column.

§ Plasmapheresis:

Plasmapheresis is used to remove excess plasma and antibody proteins from the blood if this thickens the blood and impairs circulation. Blood is drawn from the patient and passed through a machine to separate the plasma (the liquid component of the blood) from the blood cells during this treatment. The surplus antibodies are present in the patient's plasma, which is not given back to them. Along with donated plasma or a plasma replacement, the healthy blood cells are reintroduced to the bloodstream. New antibodies can still develop even after plasmapheresis Inhibitors of histone deacetylase (HDAC) are among the most promising new families of anticancer drugs. HDAC inhibitors cause cancer cell growth suppression, programmed cell death, and the reactivation of tumour suppressor gene transcription. ⁴⁰

§ Use of antibiotics:

Drugs are used in antibiotic therapy to treat cancer and illnesses brought on by bacteria and other microbes.

§ Immunotherapy:

Immunotherapy is a form of cancer treatment that activates the patient's immune system. The body's natural defenses against cancer are boosted, directed, or restored using substances that are either produced by the body or created in a lab The nuclear division index, or NDI, is a biomarker for the immune system's reaction to dietary materials. It measures a cell's viability and capacity to divide as well as its amount of cytotoxic and cytostatic effects.⁴¹One kind of cancer treatment that supports our immune system in battling cancer is immunotherapy. It functions by assisting the immune system in identifying and eliminating cancerous cells.⁴²

Fig.5: CAR T-cell therapy

CART-cell therapy:

The process by which the immune cells known as T cells of a patient are altered in a lab so that they will recognize and kill cancer cells. Blood is drawn from a vein in the patient's arm and sent through a tube to an apheresis device (not shown). This device eliminates white blood cells, including T cells, and then returns the remaining blood to the patient. As shown in fig.5. Then, in a lab, the T cells are genetically modified to contain the gene for a unique receptor known as a chimeric antigen receptor (CAR). The patient receives millions of CAR T cells by injection after being generated in the lab. CAR T cells can able to bind an antigen on the cancer cells and kill them.⁴³Ascorbic acid stimulates or maintains T cell proliferation to combat the infection by blocking mechanisms that cause T cells to undergo apoptosis.^[44]

Staging:

Following are on-Hodgkin lymphoma Stages and Categories.

· Stage I of NHL is defined as presence of one lymph node group.

· Stage II: Presence of two or more lymph node groups on the same diaphragmatic (thin muscle) side.

· Stage III: Both sides of the diaphragm's lymph node groups are involved.

· Stage IV: Possible lymph node involvement as well as participation of one or more organs other than the lymph nodes ⁴⁵As shown in fig.6

Fig.6: Location of Non-Hodgkin’s lymphoma in the body for each stage

Groups A, B, X, and E. NHL has four stages, which can be categorized.

· The A group denotes the absence of fever, excessive sweating, and weight loss in the patients.

· Patients in the B category have a fever, profuse sweating, and weight loss.

· The X classification denotes bulky illness (huge lymphocyte masses).

· The E category denotes involvement in tissues outside of but close to the major lymphatic areas, or in organs other than lymph nodes.

When referring to NHL, the term "stage IV" does not have the same importance as it does for some other cancers. NHL does not always begin at stage I and continue to stage II and beyond. Stage III or stage IV disease is detected in more than 50% of patients with moderate or aggressive disease and more than 80% of people with indolent variants of NHL. Depending on the patient's particular subtype of disease, a diagnosis of stage IV NHL may be highly treatable.

Complications:

The following are examples of possible disease-related complications:

Alternately, autoimmune hemolytic anemia is seen in some kinds of NHL (such as small lymphocytic lymphoma/chronic lymphocytic leukemia [SLL/CLL]), which are characterized by cytopenia’s (neutropenia, anemia, and thrombocytopenia) related to bone marrow infiltration.

Bleeding brought on by thrombocytopenia, disseminated intravascular coagulation (DIC), or vascular invasion by the tumor.

Infection resulting from leukopenia, particularly neutropenia.

Cardiac issues brought on by a significant pericardial effusion or cardiac metastases that cause arrhythmias.

Breathing issues brought on by pleural effusion and/or parenchymal lesions.

Large mediastinal tumor-related superior vena cava (SVC) syndrome.

Vertebral tumors that cause spinal cord compression.

Subsequent neurological issues to primary CNS malignancy or lymphomatous meningitis.

Blockage, bleeding, and perforation of the GI tract in a patient with GI lymphoma (may possibly be brought.^46-47

Therapeutic approaches:

· Rituximab:

For symptomatic individuals for whom radiation therapy is contraindicated or who would prefer an alternative course of treatment, Rituximab is an additional therapeutic option. When combined with systemic chemotherapy, Rituximab—a monoclonal antibody that targets the CD20 antigen found in both benign and malignant B-cells—has extended the duration of remission and increased patient survival for patients with indolent B-cell lymphomas when compared to chemotherapy administered alone. ^48-52

· Idelaisib:

The FDA has expedited approval of Idelalisib (Zydelig), the first PI3K inhibitor, for patients with small lymphocytic lymphoma and relapsed follicular B-cell NHL who have had at least two prior systemic treatments. Idelalisib 150 mg PO BID was administered to participants in this single-group, phase II, open-label study until the patients' disease progressed or the study was stopped. Out of 125 patients, 57% had responded, and 6% of those responses satisfied the requirements for a full response. The overall response time was 1.9 months, the median progression-free survival was 11 months, and the median response length was 12.5 months.⁵³

· Opanlisib:

Additionally, the FDA approved duvelisib and Opanlisib for the treatment of follicular lymphoma in patients who had not responded to two previous treatments. Based on a phase II trial with an objective response rate of 59% and 12% complete responses, Copanlisib was approved. 22.6 months was the median duration of response (DoR). The median overall survival was not yet attained, but the progression-free survival was 11.2 months on average.⁵⁴

· Duvelisib:

Duvelisib is a PI3K-delta and PI3K-gamma selective oral small molecule inhibitor. An overall response rate (ORR) of 47.3% was recorded in the phase II, open label, worldwide DYNAMO study. Ten months was the projected median duration of response, and 9.5 months was the anticipated median progression-free survival.⁵⁵

· Umbralisib:

When expressed on malignant B cells, umbralisib dual-inhibits both PI3K-delta and casein kinase (CK1) 1-epsilon. For FL who had received at least three lines of systemic therapy prior to relapse, as well as for refractory MZL who had at least one prior anti-CD20-based regimen, it was granted accelerated approval.

CONCLUSION:

The prognosis for non-Hodgkin's lymphoma is influenced by a number of variables, including the lymphoma's subtype, the stage at diagnosis, the patient's general health, and the efficacy of treatment. With the right treatments, like chemotherapy, radiotherapy, immunotherapy, or stem cell transplantation, many non-Hodgkin's lymphoma patients experience remission or even a cure. To check for any recurrence, it is crucial to receive regular follow-up care. People who have been diagnosed with this ailment must speak with their medical team for individualized information on their particular situation and prognosis.

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Received on 12.12.2023 Modified on 01.02.2024

Res. J. Pharmacology and Pharmacodynamics. 2024;16(2):99-106.

DOI: 10.52711/2321-5836.2024.00018