A Brief Assessment and Description of Diffuse large B-cell Lymphoma
Charles Adeniran
Cancer is a class of diseases characterized by uncontrolled cell growth. Lymphoma is a cancer of lymphocytes, which are a type of white blood cell. Lymphocytes circulate throughout the body traveling in a network known as the lymphatic system. {REF} This system usually includes the bone marrow, spleen, thymus, and lymph nodes. {REF} Organs and blood vessels are connected to the lymphatic system and work in conjunction to produce and store cells that fight bacteria, viruses and infection. {REF} There are two types of lymphomas, Hodgkin's and Non-Hodgkin's, based on the kind of white blood cell the cancer affects. {REF}
Physicians usually categorize the lymphoma between Hodgkin's lymphoma and non-Hodgkin's by examining cancer cells under a microscope. If the physician detects the presence of an abnormal Reed-Sternberg cell, the lymphoma is classified as Hodgkin's. {REF} If the Reed-Sternberg cell is not present, the lymphoma is classified as non-Hodgkin’s. Diffuse large B-cell lymphoma (DLBCL) is a very common subtype of Non-Hodgkin Lymphoma (NHL) accounting for approximately 30% to 40% of all cases. {REF}
In 2017, it was reported that there were an estimated 72,240 NHL new cases. {SEER} There is expected to be 74,680 new cases in 2018. {SEER} Approximately 4.3% of all new cancer patients were NHL cases. {SEER} There were approximately 20,120 deaths in 2017 due to NHL, this accounted for about 3.4% of all cancer deaths. {SEER} Based on data from 2010 to 2014, there are 19.5 new cases for every 100,000 men and women that get diagnosed with NHL. {SEER} Approximately 2.1% of men and women will be diagnosed with NHL at some point in their lifetime. {SEER} Also based on the same data from 2010 to 2014, there is approximately 661,996 people living with NHL. {SEER} The percent of patients with DLBCL are that expected to survive after 5 years is 71.4%. {REF}
The Revised International Prognostic Index (R-IPI) succeeds the International Prognostic Index (IPI) which was developed to help determine the outcome for patients with aggressive high-grade lymphoma. The R-IPI helps physicians to assign people to risk groups based on the number of poor prognostic factors they have. The R-IPI divides patients into 3 risk groups using factors: age, stage, lactate dehydrogenase level (LDH), extranodal spread, performance status. Patients with a normal level of LDH in their blood tend to have a better prognosis than those with higher LDH levels. A high level of LDH usually means a more advanced cancer. LDH is often higher in people with a high-grade lymphoma. Performance status measures how well a person can do ordinary tasks and daily activities. The more active a person, the more able they are to continue their normal activities of daily living and therefore better performance status. A patient with a good performance status usually has a better prognosis than patients with a poor performance status.
The risk group is determined by counting with points; 1 point for each poor prognostic factor. The lower the number of prognostic factors, the more favorable the prognosis. A very good prognosis has no poor prognostic factors. A good prognosis has 1 or 2 poor prognostic factors. A poor prognosis has 3 or more poor prognostic factors.
Commonly reported symptoms exhibited patients with diffuse large B-cell lymphoma are swelling of the lymph nodes in the neck, groin, stomach, or armpits which can occasionally be painless. Lumps can grow quickly over a period in as little as a few weeks. Occasionally, other parts of the body are affected. When this occurs, it is described as an extranodal disease meaning that the cancer is causing effects outside of the lymph nodes, and can include the stomach or bowel being affected, which may cause abdominal discomfort or pain, diarrhea or bleeding. DLBCL can also be found in many other areas including the salivary glands, nasal sinuses, liver, lungs, testes, skin, brain or eye with symptoms being directly related to the amount of pressure the lymphoma is putting on the particular body part that is affected. Other symptoms include tiredness, shortness of breath, weight loss, night sweats, and high body temperature/fevers.
There are other criteria that can affect a person's likelihood of developing DLBCL, and they are age, gender, and ethnicity. It is not an inherited disease, siblings and children of patients with DLBCL do not have an increased risk of developing the disease. DLBCL has been found in patients with a range of age groups. Although, the disease is more commonly found in people who are middle-aged or elderly with an average age of diagnosis near 60 years of age. Men are more likely to develop this disease than women. Also, in the United States, Caucasians are more likely to develop DLBCL than Asians or African Americans.
Diagnosis for NHL is generally the same across this subclass of disease. A biopsy is performed by removing part or all of an enlarged lymph node and sometimes from other body tissues to examine the cells under a microscope. Additional tests may be necessary which may include blood tests, x-rays, CT or PET/CT scans, or bone marrow biopsy where samples are taken and then used to get more information about the type of lymphoma.
These additional tests are sometime called Staging tests and can help determine which areas of the body have been affected by DLBCL. The Staging process involves dividing patients into stages based upon how much of the lymphatic system is affected at the time of diagnosis. The term, Lymph node regions is known as an area of lymph nodes and the surrounding tissue. Lymph structures are the organs or structures that are part of the lymphatic system, they include the lymph nodes, spleen, and thymus gland.
Stage I is defined where only one lymph node region is involved, this could be an instance where one lymph structure is affected, or only one extranodal site is affected. Stage II is defined as two or more lymph node regions or lymph node structures on the same side of the diaphragm are affected. Stage III is defined where a lymph node region or structure on both sides of the diaphragm are affected. Lastly, Stage IV is described as widespread involvement of a number of organs or tissues other than lymph node regions or structures, such as the liver, lung, or bone marrow. When a stage is determined, it also includes a letter to denote symptoms the patient may also exhibit, for example, fever, weight loss, or night sweats. A would mean that symptoms are not present, while B means they are present.
Physicians and scientists have conducted genomic studies on DLBCL and have noted lesions that have affected histone/chromatin acetyl-transferase and methyltransferase enzymes.
Notable mutations or deletions inactivating CREBBP and EP300 have been detected in up to 35% of patients with DLBCL. {REF} CREBBP mutations lead to truncations of the C-terminal HAT domain or to amino acid changes that impair its ability to acetylate BCL6 and p53, leading to constitutive activation of the oncoprotein and to decreased p53 tumor suppressor function. The regulation of BCL6 and p53 is very important for DNA damage responses in the cell. One consequence of increased BCL6 activity overtaking p53 is an increased tolerance for DNA damage in the context of impaired apoptotic and cell cycle arrest responses. The identification of mutations in CREBBP and EP300 may have direct therapeutic implications in view of current attempts to use histone deacetylase inhibitors (HDAC) as anti-cancer drugs.
The p27 protein is a cyclin-dependent kinase (CDK) inhibitor found to be involved in G1 cell arrest, differentiation, apoptosis, and chemotherapeutic response. {Seki} There has been studies that show high expression of p27 is associated with shorter OS and DFS; other than the high expression, there was no correlation between p27 expression and patient survival. {Seki} The prognostic power of p27 expression did not appear to affect R-IPI scoring. {Seki} Furthermore, these authors noticed that high expression of Skp2, an F-box protein that promotes p27 ubiquitination and degradation, is associated with shorter OS of DLBCL patients.
The cyclin D family of proteins mediate the transition of cells from G1 to the S phase by activation of the CDK4 and CDK6. {REF} A recent study demonstrated that high tumor expression of cyclin D3 is associated with a significantly lower complete remission (CR) rate and shorter 3-year OS. {REF} The power of cyclin D3 expression to predict CR and survival was IPI independent. {REF} Similarly, the expression of cyclin D2 has been associated with worse outcome, both as an isolated gene and in multiple gene models. {REF}
Ki-67 is a nuclear antigen expressed by dividing cells. The percentage of KI-67–expressing cells reflects the proportion of the tumor cells that are actively cycling and dividing. The prognostic significance of Ki-67 staining in DLBCL is controversial. There appears to be prognostic significance of Ki-67 staining in 60 representative DLBCL patients from a group study that compared four different anthracycline-based regimens. {REF} The 3-year OS was significantly shorter in patients with Ki-67 nuclear expression in 80% or more malignant cells. {REF} In a subsequent study on 105 DLBCL patients, the same authors demonstrated that high proliferative activity, defined in this study as nuclear Ki-67 expression in greater than 60% of malignant cells, was a strong predictor of poor survival. {REF} The reason for the different cutoff for Ki-67 positivity in these two studies reported by the same group of investigators is unclear. {REF} A different group study also evaluated the role of Ki-67 in DLBCL patients. {REF} Low expression of Ki-67 was defined as less than 60% and was detected in 63% of the tumors.
Expression of Ki-67 was not associated with significant differences in the 5-year OS. {REF} Additional studies also failed to confirm the prognostic value of Ki-67 expression in DLBCL patients. {REF} One possible explanation for the incongruence in the reported results is the use of different definitions for Ki-67 positivity and negativity. Another possible explanation is the complex relationship between Ki-67 expression and outcome. {REF} Tumors with low Ki-67 index may exhibit resistance to chemotherapy, given that majority of the malignant cells are in G0/G1 and thus are resistant to cycle-specific cytotoxic chemotherapy. {REF} Furthermore, G0/G1-arrested cells have time to repair DNA damage induced by the chemotherapy and thus survive. {REF}
DLBCL is high-grade or fast growing and needs to be treated immediately. The preferred treatment is chemotherapy which consists of the monoclonal antibody rituximab (Rituxan) and a regimen of CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisone). {REF} Collectively this regimen is known as R-CHOP. In most patient cases, CHOP can be administered in 14 or 21-day intervals. {REF} This treatment usually continues for approximately 4 months. Physicians typically will conduct restaging after 4 cycles of CHOP or R-CHOP and if necessary, again at 6 cycles. {Armitage} It was shown that adding rituximab to CHOP chemotherapy improved outcomes. Despite CHOP and R-CHOP advances, the cure rate is 60% of patients with DLBCL, leaving 40% of patients who still die of their disease. {REF}
EXPAND ON OTHER DRUGS
In some studies, a different R-ACVBP regimen has shown to be superior to R-CHOP in younger patients between the ages of 18-59 years. {Recher, Reyes}
R-ACVBP includes rituximab, doxorubicin, cyclophosphamide, vindesine, bleomycin, and prednisone. {REF}
R-EPOCH includes Rituximab, Etoposide Phosphate, Prednisone, Vincristine Sulfate (Oncovin), Cyclophosphamide, Doxorubicin Hydrochloride (Hydroxydaunorubicin)
Rituximab binds with high affinity and specificity to the CD20 antigen, which is expressed on the vast majority of malignant B cells. The apparent affinity constant of rituximab for human CD20 is approximately 5.2 nmol/L. {REF} At least four mechanistic pathways are thought to be responsible for the elimination of CD20+ cells by rituximab antibody-dependent cellular cytotoxicity (ADCC), antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity (CDC), and direct antitumor effects via either apoptosis or other cell death pathways. {REF} Binding of the fragment crystallizable (Fc) portion of the rituximab mAb to tumor cells results in the reorganization of CD20 molecules into lipid rafts and subsequent activation of the classical pathway of the complement cascade. This leads to CDC, including tumor cell lysis and augmentation of phagocytosis. ADCC occurs as a result of an interaction between the Fc portion of rituximab in antibody-coated tumor cells and membrane-bound Fcγ receptors expressed on the surface of effector cells (natural killer cells, granulocytes, and macrophages). {REF} This interaction triggers the onset of cellular immune responses central to ADCC, including the release of cytokines, chemokines, and mediators that kill target cells. In addition, rituximab binding to CD20 on B lymphocytes is thought to induce cell death via nonclassical apoptosis by triggering the crosslinking of multiple CD20 molecules.
The most common side effects from the use of rituximab combination therapy are:
irritation around the intravenous or port site, red or pink urine for a few days due to doxorubicin, appetite changes, weight changes, indigestion, nausea/vomiting, fatigue, sleeping difficulties, low blood counts, anemia, nose bleeds, a runny nose, bleeding gums, mouth sores
mouth ulcers, hair loss, loss of menstruation or amenorrhea, a loss of fertility, early menopause, skin sensitivity, nerve problems, or neuropathy. Less commonly observed side effects are skin rash due to an allergic reaction, burning or painful urination, changes in taste, changes to fingernails and toenails, changes to heart muscles, and diarrhea.
Rare side effects include changes to lung tissue and there is always the possibility of developing another type of cancer.