Living with NHL

What makes one susceptible to developing NHL?
The reasons that make certain individuals susceptible to developing non-Hodgkin’s lymphoma are not currently understood. There are certain risk factors that may increase your chances of getting NHL. However, having one or more risk factors is not a certainty to developing NHL.¹ Risk factors, based on whether they are modifiable or not, are tabulated here.

Non-modifiable Risk Factors	Modifiable Risk Factors
Age (>60 years)	Radiation
Gender (Male sex)	Chemical Exposure (Pesticides, Chemotherapy drugs)
Race/Ethnicity (Caucasians have higher risk)	Obesity
Family History (Parent, child, sibling of a person with NHL at higher risk)	Tobacco Smoking and Alcohol
Autoimmune Diseases (eg, Crohn's disease, Lupus, etc.)	Breast Implants
Immunosuppression or a weakened immune system	Vitamin D Deficiency
	Infections such as HCV or H. pylori

Early symptoms of NHL

Many patients, especially those with follicular lymphoma, marginal zone lymphoma, and indolent subtypes, do not show any signs or symptoms of non-Hodgkin’s lymphoma.

Others might present with one or more of the following:^3-4

Swollen lymph nodes
Fever*
Night sweats*
Tiredness
Shortness of breath or cough
Severe or frequent infections
Easy bruising or bleeding
Swollen abdomen
Feeling of fullness after only eating a small quantity of food
Unexplained weight loss*

*A triad of symptoms known as B symptoms
Since these are not specific symptoms to non-Hodgkin’s lymphoma, diagnosis based on these alone, cannot be madee^.5

NHL Diagnosis

Your doctor will perform one or more of the following:

Complete medical history including your symptoms, risk factors, and any other medical conditions
Physical exam, where attention will be given to your lymph nodes to eliminate the likelihood of infections
Blood tests including complete blood count (CBC) that may show abnormal cell counts and anemia, and serum chemistry tests such as lactate dehydrogenase (LDH)
Lymph node and/or tissue biopsy: This is the only way to confirm a diagnosis of NHL. In many cases, a swollen lymph node is due to infections, and therefore the doctor will probably give you a course of antibiotics and wait a few weeks to see if the lymph nodes shrink. The doctor will use his expertise to determine if the size, texture, or location of the enlarged lymph node requires an immediate biopsy. Biopsy samples will be examined by a pathologist under a microscope to identify the type of lymphoma. Flow cytometry and immunohistochemistry are performed for immunophenotyping, ie, to find out the type of lymphoma based on the presence of certain proteins on the cell surface. Chromosome tests help to identify changes in the chromosome which can be useful for the identification of the type of lymphoma.
Imaging may be recommended in some cases for staging of the lymphoma. For eg, CT of the neck, chest, or abdomen, PET scan of a lymph node, MRI of the brain, or ultrasound imaging of the testicular area.⁶
Lumbar puncture: In case of highly aggressive NHL such as DLBCL with a high CNS involvement, this might be recommended, with a sample sent for microscopic observation.
Pleural or peritoneal fluid sampling: Pleural (inside the chest) or peritoneal (inside the abdomen) fluid may have to be removed when the lymphoma has spread to these areas causing fluid to build. This is done via thoracentesis or paracentesis, respectively.⁷

For further information on how these individual diagnostic tests are performed, please refer to the Resources section.

NHL staging

NHL staging is a way to determine where the cancer is, and how much it has spread to other sites. Staging also allows the doctor to decide on the best course of treatment.¹ Staging consists of two divisions (limited or advanced) and four stages (I to IV). Broadly, stages I and II are limited disease, while stages III and IV are advanced disease.

Lugano classification¹
Stage 1	Involvement of a single lymph node or group of adjacent nodes
Stage 2	Involvement of two or more groups of nodes on the same side of the diaphragm
Stage 3	Involvement of lymph nodes on both sides of the diaphragm and/or spleen
Stage 4	Disease is widespread to lymph nodes, organs, and bone marrow.

Current treatments for NHL

Several kinds of treatment are currently available to treat NHL. Treatment choices depend on the specifics of your lymphoma including the type and location of your lymphoma and whether it is aggressive or indolent. Note that an indolent lymphoma may not need immediate treatment and your doctor may recommend a wait-and-watch approach, monitoring the cancer to see if it is advancing. Your doctor will provide you with options based on your overall health and preferences.

Treatments are broadly divided into the following five categories:

Chemotherapy is used to destroy fast-growing cancer cells and is the main treatment for NHL, given orally or intravenously. Chemotherapy drug(s) are typically given in a series of cycles over a set period. The most common course of chemotherapy is called CHOP and consists of 4 medications: cyclophosphamide, doxorubicin, prednisone, and vincristine. Often, a monoclonal antibody called rituximab (R-CHOP) or obinutuzumab (O-CHOP) is added to this regimen. Other chemotherapy regimens include other drugs including a combination with bendamustine and rituximab, fludarabine, and R-CVP (rituximab, cyclophosphamide, prednisone, vincristine).⁸ Chemotherapy may also be used to prepare your body for bone marrow transplant/stem cell transplant.⁹

Radiation therapy utilizes high-energy beams such as X-rays or protons to destroy cancer cells. Radiation can be used alone to destroy one or two targeted spots that contain cancerous lymphoma and can be used post-chemotherapy to destroy any lymphoma cells that remain.⁹

Immunotherapy boosts the patient’s own immune system to fight cancer. This includes the use of modified T cells and checkpoint inhibitors. In chimeric antigen receptor (CAR) T cell therapy (CAR T) some of the patient’s own T cells are removed and modified to contain specific proteins called receptors. The receptors allow these modified T cells to recognize cancer cells that have the target protein that binds to these receptors. These modified T cells are grown in a lab and then returned to the patient’s body. Currently, available FDA-approved CAR T therapies include Axicabtagene ciloleucel, Tisagenlecleucel, Brexucabtagene autoleucel, and lisocabtagene maraleucel.

Immune checkpoint inhibitors block pathways to stop or slow cancer growth. Pembrolizumab is an example of such an inhibitor.⁸

Targeted drug therapy is just what the name implies. It targets cancer-specific genes or proteins that are involved in cancer growth.
Monoclonal antibodies such as rituximab target a protein called CD20 on the surface of B-cells, both normal and cancerous. The attachment of rituximab to CD20 activates the patient’s immune system. Other monoclonal antibodies include obinutuzumab and ofatumumab which target CD20.

Radiolabeled antibodies targeting CD20 such as ibritumomab tiuxetan help focus the radiation directly on the NHL.

Antibody-drug conjugates like brentuximab attach to cancer cells and release a drug directly into the tumor cells. Other antibody-drug conjugates include loncastuximab tesirine-lpyl that targets CD19, polatuxumab vedotin piiq that targets CD79b, and tafasitamab-cxix that targets CD19 and is used in combination with lenalidomide to treat recurrent or refractory DLBCL.⁸

Other targeted FDA-approved therapies for the treatment of NHL include ibrutinib, acalabrutinib, and zanubrutinib (Bruton tyrosine kinase pathway), venetoclax (Bcl2 inhibitor), copanilisib, idelalisib, and duvelisib (PI3 kinase inhibitors), Selinexor (nuclear export inhibitor), lenalidomide (immunomodulatory drug), tazemetostat (EZH2 inhibitor), belinostat, romidepsin, and vorinostat (histone deacetylase inhibitors), and bortezomib (proteasome inhibitor).¹ Further details on each of these therapies can be accessed in the Resources section.

Bone marrow transplant/Stem cell transplantation involves using high doses of radiation and chemotherapy to suppress the patient’s bone marrow and immune system. Fresh and healthy bone marrow is then infused into the patient’s blood to travel to the bone marrow to regenerate healthy bone marrow. Depending on the source of the bone marrow, the transplant may be considered autologous (patient’s own stem cells) or allogenic (donor stem cells).^1,8