The clinical condition given was a 33 year old patient diagnosed with chemotherapy resistant advance follicular lymphoma. Lymphoma is a type of cancer of the lymphocytes, which belongs to the white blood cell family of the body.1 White blood cells circulate the body through an extensive network of lymphatic systems, illustrated in figure 1, which includes the bone marrows, spleen, thymus and the lymph nodes.
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Lymphoma is categorized into two, the Hodgkin lymphoma and the non-Hodgkin lymphoma (NHL). Follicular lymphoma belongs to the group of NHL that affects the B-cell lymphocytes, which plays a critical role in immune response by producing antibodies in human body. Under the view of a microscope, follicular lymphoma produces a nodule or follicular structure, as the name suggested. Microscopic image of follicular lymphoma can be seen in figure 2.
Diagnosis requires a biopsy of a lymph node, involving the process of obtaining a small amount of tissue for testing in the laboratory.5, 6 However, biopsy alone will not be sufficient to diagnose the lymphoma. Other scans on the abdominal, chest, or pelvic areas by using techniques such as Computer Tomography Scan (CT-Scan), Positron Emission Tomography (PET-Scan), will aid diagnosis as well.7, 8 According to the National Comprehensive Cancer Network (NNCN) Guidelines, laboratory test which is inclusive of full blood count, uric acid level, serum calcium level, as well as liver function test are needed in order to confirm diagnosis.9
Follicular Lymphoma Stages and Classifications
Staging is important in patient with follicular lymphoma as it divides patient into group and determines what kind of treatment is needed, or whether treatment is required. Generally, NHLs are divided into four stages, summarized in table 1 below. Follicular lymphomas categorized in stage II, III, and IV are termed as “advanced” follicular lymphoma, as the case of the patient in the scenario. 5, 6
Table 1: Stages of NHL in terms of regions involved.
- Only one of the lymph node is involved
- Two or more lymph nodes from the same side of diaphragm are involved
- Lymph nodes at both sides of the diaphragm are involved
- Involves a number of lymph nodes, tissues or organs
Furthermore, lymphomas can generally be described as Low Grade, Intermediate Grade, or High Grade, depending on the speed they grow, based on the Revised European-American Lymphoma (REAL) grading system1, 6. Generally, low grade lymphomas are slow growing, while high grade lymphomas are characterized by rapid growing tumor cell which requires aggressive treatment compared to low grade and intermediate grade lymphomas. Ironically, many High Grade lymphoma can be cured, while low grades lymphoma tends to reappear and contribute to relapses.6
Apart from the general lymphomas grading, follicular lymphomas have their own grading system, which are separated into three grades. According to the World Health Organization (WHO), the follicular lymphomas are categorized according to the number of centroblast (large follicular cell) present while the tumor was scanned by using the highest power of magnification on the microscope.1, 5, 6 The grades were summarized in table 2.
A research done by Bosga-Bouwer et al. over 30 patients indicates that genetic factors are the primary causes of follicular lymphomas. The research used southern blotting technique, polymerase chain reaction, and fluorescence in situ hybridization to confirm a translocation in the chromosome 14 and 18, which affects the bcl-2 proto-oncogene, and the main function of bcl-2 gene’s is to prevent apoptosis of B-cell lymphocytes.10 Overexpression of the bcl-2 gene results in prolonged survival rate of the cell due to the prevention of programmed cell death.1, 10
Signs and Symptoms
Symptoms of follicular lymphoma include adenopathy, night sweats, weight loss, and fever. Adenopathy represents painless swelling in one the lymph nodes. Another important indicator includes elevated levels of Lactate Dehydrogenase (LDH), an enzyme that facilitates the conversion of pyruvate to lactate. 11 However, it is important to note that some of the patient lymphoma will be asymptomatic.
Follicular lymphoma will further complicate by increasing tumor bulk and threaten end-organ function. After a given period of time, it might transform into a more rapid growing lymphoma- the diffuse large B-cell lymphoma (DLBCL). In contrast, DLBCL is a much more aggressive form of NHL. According to a research done by Horning and Rosenberg, 25% to 60% of the patient will transform from follicular lymphoma into DLBCL12. A paper done by Lossos et al. suggested that the transformation to DLBCL includes multiple genetic mechanisms – no single gene is responsible for the transformation13. Apart from that, another paper by Montoto from Cancer Research UK Medical Oncology Unit, demonstrates that the risk will be significantly higher (P-value = 0.02) if a patient was in an advanced stage of follicular lymphoma, which is the situation present in the case scenario14. It was also found that there are no statistically significant differences between the time of initiation of therapy and chances of transforming from follicular lymphoma into DLBCL. If a patient with DLBCL is not treated accordingly, it is often fatal 5, 14.
Furthermore, tumor of follicular lymphoma might relapse and further develop into chemotherapy resistant follicular lymphoma. Chemotherapy resistant lymphoma occurs when the lymphoma that has been responding to chemotherapy had begun to grow, resisting the effects of the therapy. The resistances are acquired through a number of mechanisms, namely genetic transformation of the B-cells. When this occurs, as seen in the case, the treatment option will be narrowed down, since chemotherapy is no longer an option.15
Incidence, Morbidity, and Mortality Rate
Follicular lymphomas have an incidence rate of 2500 cases each year in the UK.16 It exhibits the second highest incidence rate among all the lymphomas, with the first being DLBCL. 17 It dominates 30% of all the NHL and it is the most common type of Low Grade NHL.1, 17
Prognosis Index is used to predict the treatment options and outcome of follicular lymphoma. A Follicular Lymphoma Prognosis Index, developed by Solal-Celigny, is currently being used internationally18. This prognosis index takes into account of 5 factors, which are age (>60 years), stages of follicular lymphoma (stage III & IV), hemoglobin levels (low), numbers of lymph nodes/organs affected (>4), and levels of LDH (high) 17, 18. 91% of patient which suffers none of the abovementioned factors will live longer than 5 years. If the patient suffers from two or three of the factors in Follicular Lymphoma Prognosis Index, the rate of living longer than 5 years will drop to 78% and 43% respectively 18.
In the UK, the median age of onset of follicular lymphoma was 60 years old, as compared to 67years old in the United States (US) 16, 19. In the US, according to the National Cancer Institute, rate of mortality was the highest among those from 75-84 years old, with a death rate of 33.7%. However, in those patient aged from 20-34 years old (case scenario patient aged 33years) mortality rate was only 1.6%. The average death rate of patient with NHL was 7.1 per 100,000 men and woman per year in the US19.
Evidence Based Treatment Options of Follicular Lymphoma
Follicular lymphoma can be considered incurable, but fortunately the growing tumors are sensitive to radiation and chemotherapy. Treatment options of lymphomas are highly based on severity of the symptoms and stages of lymphoma.5,20 If patient is asymptomatic, prescribers often employs a “wait and watch” approach, and according to studies, there is no difference in the survival rate between patients who were treated earlier and patients who were treated according to “wait and watch” method. 20 Treatments options are summarized in table 3.
- Uses ionizing radiation to destroy cells
- Uses drugs to stop or slow down the growth of cells
- Uses proteins that targets rapid growing cells
- Radioactive isotopes combined with monoclonal antibodies
Bone Marrow Transplant
- Transplantation of stem cells
One of the ways to treat follicular lymphoma is by performing radiotherapy, which is also called radiation therapy. It was preferably use in Stage I or Stage II of the lymphomas which are localized.20, 21 The mechanism of radiotherapy includes usage of ionizing radiation such as beta and gamma rays to destroy the tumor cells and impairs their growth, while the body removes them through a natural process.
Currently, the method employed in treatment of lymphoma tumor is known as the external beam therapy. 20, 21, 22 External beam therapy is done from a machine outside the patient, which is known and the linear accelerator. Radiation to body parts above the diaphragm is known as Mantle Field radiation, while radiation to parts below the diaphragm is known as Inverted Y-field radiation.22 A study by Aviles has shown that survival rate of a patient treated with radiotherapy for a 5 years period was 48%, and if used together with chemotherapy, the patient’s survival rate will be increased to 83%.23, 24 According to another research by MacManus, 40% of the radiotherapy patient remained disease free after 10 years.
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Chemotherapy involves the usage of drugs to stop or slow down the growth of lymphoma B-cells, hence managing the lymphomas’ symptoms.5, 6 Chemotherapy drugs only target specific rapid-growing cells such as tumor cells, and impairs their ability to multiply and growth. 20 However, many cell lines in patients such as bone marrow, hair follicles, and the lining of the gastrointestinal tract are rapid-growing cells and therefore, it will be targeted by chemotherapy drugs as well, causing the side effects.
Initial responses towards chemotherapy are usually high, and therefore, it is considered as the first line-treatment in treating NHL.20 Many protocols of chemotherapy combination were proposed, with the common ones being the CHOP and CVP.
CHOP therapy includes the usage of four drugs- Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone while CVP therapy uses Cyclophospharmide, Vincristine, and Prednisone.5, 6, 20 A research by Fisher had concluded that CHOP should be used as first line treatment for advanced grade non-Hodgkin lymphoma, with a result of 44% survival rate in 1138 patient after a period of 3 years.26 However, a more recent study by Hiddemann suggested that the use of Rituximab, a monoclonal antibody, together with CHOP greatly improves the response rate of patient to 96% (P-value of 0.011), and reduce the chances of treatment failure by 60%. The study, which was done on 2005, proves that R-CHOP is the superior frontline treatment of choice for advanced follicular lymphoma compared to CHOP.
According to the British National Formulary 57 (BNF 57), the usage of CHOP will produce side effects such as oral mucositis, hyperuricaemia and tumour lysis syndrome. Nausea and vomiting is also the common side effects of chemotherapy drugs, and it may lead to refusal of further treatment. Bone marrow suppression and alopecia are also of the core problems of chemotherapy drugs.
Monoclonal Antibody Therapy
Monoclonal antibody therapy works by using antibodies that sticks to the surface of specific groups of cells, such as cancer cells, and trigger the body’s natural immune system to destroy these cells. 5 The advantages of monoclonal antibody compared to chemotherapy is that they are more specific compared to chemotherapy.
Rituximab is used to treat follicular lymphoma, due to the mechanism of action of binding to CD20 protein- the abundant protein on the surface of B-cell. Rituximab causes the death of the cell by the induction of apoptosis. 29 According to the BNF 57 and North London Cancer Guideline, Rituximab is used to treat stage III and IV follicular lymphoma, or in those patient that had a relapse after treatment of chemotherapy, or those that other treatment options are exhausted.16, 28 Nice guidelines recommends that Rituximab should be given as a third-line treatment, and should only be given as first line with combination of chemotherapy to patient with stage III and IV follicular lymphoma.
A meta-analysis research by Vidal et al. reveals that when Rituximab was given as a maintenance therapy, it significantly improves overall survival rate and the relapse rate of patient, compared to patient that did not have Rituximab as maintenance therapy.29, 30 Another research by Hauprock and Hess indicates that Rituximab improves survival rate if given as relapse therapy and maintenance therapy.31 When given together with CHOP chemotherapy, it greatly improves the overall outcome of a patient.
Adverse side effects of Rituximab appears to be infusion related side-effects, namely the cytokine release syndrome, which is characterized by fever, chills, nausea and vomiting, as well as tumor pain.
Radioimmunotherapy consist of one radioactive isotope and a monoclonal antibody to assist specific cell targeting. The radioactive isotope which is attached to the antibody will release radiation once the antibody is bound to the specific cell type, hence killing the cells.21, 32 This method is considered to be a more advance therapy compared to chemotherapy and monoclonal antibody therapy.
There are two drugs available now in radioimmunotherapy, namely Bexxar and Zevalin.32, 33 Zevalin consist of two radioactive isotopes called indium-111 and yttrium-90. The purpose of indium-111 in the drug is to enables physician to view the paths of the drug in the body, while yttrium-90 is the therapeutic portion of the drug. Zevalin is administered via the intravenous route together with Rituximab over a time of ten minutes, over a course of a week.
The main side effect of Zevalin is lowered blood cell count, normally observed 4-6 weeks after the treatment. However, Zevalin is considered to be advantageous in terms of side-effects as it does not exhibits the normal side-effects of chemotherapy drugs, such as alopecia, nausea and vomiting.
In a clinical trial involving patients with NHL, Zevalin manage to produce a response rate of 70-80%. Furthermore, in the same trial, Zevalin produces responses in patient who no longer respond to chemotherapy and Rituximab.32 A review by WitZig showed a response rate of 82% to Zevalin in patient with low grade NHL. The advantages of Zevalin Therapy are that it only uses a single dose of radiation and it is being well tolerated by the patient, which was proven in the study.34 In another randomized controlled trial done by WitZig and Gordon et al., Zevalin was proved to be more superior than Rituximab, with an overall response rate of 80% compared to 55% in treating follicular lymphoma.
Apart from that, another immunotherapy drug called Bexxar, is a combination of Tositumomab and Iodine I 131 Tositumomab. Tositumomab is a monoclonal antibody targeting the CD20 protein in the B-cell Lymphoma, while Iodine I 131 Tositumomab is a radiolabeled derivative of the monoclonal antibody. Beta-radiation released by Iodine 131 is responsible for killing of the tumor cells. Bexxar is given in two different sets of intravenous infusion, two weeks apart.
Common side-effects of Bexxar include suppression of bone marrow, which is characterized by low blood counts. Bexxar might also cause hyperthyroidism and anti-murine antibody formations.
A research done by Kaminski et al. shows that Bexxar produces a very high response rate of 95% in 76 patients who enrolled in the study. 75% of the patient in the study still had a complete remission even after 5 years. This research of Bexxar rivals any kind of therapy previously used in treating follicular lymphoma, including chemotherapy, as Bexxar therapy will be completed in just one week, and proves to be more effective. Another study, by Jacene, comparing Bexxar and Zevalin, reveals that Bexxar will cause less bone marrow suppression compared to Zevalin, although both were generally well tolerated.
Treatment Recommendation for Patient in Case Scenario
According to the patient in the case scenario given, he is currently 33 years-old and he developed chemotherapy resistant advanced follicular lymphoma recently. “Advanced follicular lymphoma” indicates that his condition is in either stage III or IV, involving lymph node on both sides of the diaphragm and/or organs. In this case, since the follicular lymphoma developed resistance, chemotherapy is no longer an option.
According to the BNF and the NICE guideline, Rituximab monotherapy could be given to patients who have relapsed stage III or IV follicular lymphoma, which developed resistance to chemotherapy. 28, 29 It is recommended that the patient takes 375mg/m2 of Rituximab over a period of 21 days, according to the instructions in NICE guideline. The patient has to be on it for 8 cycles which is approximately 6 months.
Rituximab was proved to induce better response and improve overall survival rate in follicular lymphoma patient according to the meta-analysis of randomized trial performed by Vidal et al. and another study done by Hauptrock and Hess (mentioned above in treatment). Another study by Monila further supports the usage of Rituximab as it increase both response rate and survival rate as well as improving the long-term prognosis of follicular lymphoma patient. All these evidence validates the treatment option of using Rituximab in the patient.
The cost of Rituximab based on the evaluation of Assessment Group Model in the NICE guideline is approximately £8500 per life year gained in patient younger than 60 years-old and £9700 per life year gained in patient aging 60 years-old and above. It is considered cost effective based on the evaluation of the NICE guideline.
If treatment using Rituximab proves to be unsuccessful, radioimmunotherapy drug Bexxar will be recommended. Although Bexxar is still considered a new drug, the clinical trials done by Kaminski shows a remission rate of 75%. Bexxar had also been evaluated in one of the study, which shows that 86% of the patient achieved a complete response in Stage III and IV follicular lymphoma.
In conclusion, patient with chemotherapy resistant advanced follicular lymphoma should be treated with Rituximab, followed by Bexxar and Zevalin. All in all, with the new advances in radioimmunotherapy, the joint effort of health care professionals and the utilizing of guidelines with evidence-based research, patient with the follicular lymphoma, although incurable, will still be able to lead a healthy and fruitful life.
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