Sunday, March 31, 2019
Follicular Lymphoma Case Study
follicular Lymphoma Case StudyThe clinical presumption abandoned was a 33 punctuate old persevering diagnosed with chemotherapy broad toss follicular lymphoma. Lymphoma is a type of finishcer of the lymphocytes, which belongs to the white profligate cubicle family of the body.1 White blood cells circulate the body through an drawn-out network of lymphatic sy understructures, illust dictated in work up 1, which includes the bone up marrows, spleen, thymus and the lymph nodes.Lymphoma is categorize 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 insubordinate response by producing antibodies in human body. Under the view of a microscope, follicular lymphoma produces a nodule or follicular structure, as the constitute suggested. Microscopic im eld of follicular lymphoma can be seen in figure 2.DiagnosisDiagnosis requires a biopsy of a lym ph node, involving the process of obtaining a down(p) amount of tissue for testing in the laboratory.5, 6 However, biopsy alone al dispirited not be sufficient to diagnose the lymphoma. Other scans on the abdominal, chest, or pelvic areas by using techniques such as Computer mental imagery Scan (CT-Scan), Positron Emission Tomography (PET-Scan), pull up stakes aid diagnosing as well.7, 8 tally to the National Comprehensive Cancer net profit (NNCN) Guidelines, laboratory test which is inclusive of full blood count, uric battery-acid level, serum calcium level, as well as liver exercise test are needed in order to confirm diagnosis.9Follicular Lymphoma Stages and ClassificationsStaging is primal in tolerant with follicular lymphoma as it divides affected role into group and determines what kind of interposition is needed, or whether preaching is required. Generally, NHLs are dual-lane into four presents, summarized in table 1 below. Follicular lymphomas categorized in a cademic degree II, lead, and IV are termed as advanced follicular lymphoma, as the case of the persevering in the scenario. 5, 6Table 1 Stages of NHL in terms of regions affect.StagesDescriptionsStage IOnly one of the lymph node is involvedStage IITwo or more lymph nodes from the same spot of diaphragm are involvedStage IIILymph nodes at both(prenominal) billets of the diaphragm are involvedStage IVInvolves a identification quash of lymph nodes, tissues or organsFurthermore, lymphomas can in general be described as down in the mouth Grade, Intermediate Grade, or High Grade, depending on the speed they grow, pitch on the Revised European-American Lymphoma (REAL) grading system1, 6. Generally, low grade lymphomas are unwind growth, tour high grade lymphomas are characterized by rapid growing tumor cell which requires aggressive word compared to low grade and fair grade lymphomas. Ironically, many High Grade lymphoma can be cured, while low grades lymphoma tends to re appear and contribute to change states.6Apart from the general lymphomas grading, follicular lymphomas gull their own grading system, which are sepa governd into three grades. According to the existence 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 former of magnification on the microscope.1, 5, 6 The grades were summarized in table 2.CausesA explore make by Bosga-Bouwer et al. over 30 patients indicates that genetic factors are the simple causes of follicular lymphomas. The explore apply southern blotting technique, polymerase chain reaction, and fluorescence in situ crossbreed to confirm a translocation in the chromosome 14 and 18, which affects the bcl-2 proto-oncogene, and the main function of bcl-2 genes is to prevent apoptosis of B-cell lymphocytes.10 Overexpression of the bcl-2 gene results in prolonged survival deem of the cell due to the prevention of programmed cell death.1, 10Signs and SymptomsSymptoms 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 let down that some of the patient lymphoma lead be asymptomatic.ComplicationsFollicular lymphoma leave nevertheless complicate by increasing tumor bulk and threaten end-organ function. subsequently a presumptuousness period of m, it might transform into a more rapid growing lymphoma- the diffuse large B-cell lymphoma (DLBCL). In contrast, DLBCL is a a great deal 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 reputation done by Lossos et al. suggested t hat 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 stop of follicular lymphoma, which is the situation present in the case scenario14. It was similarly found that there are no statistically significant differences between the cartridge holder of initiation of therapy and chances of transforming from follicular lymphoma into DLBCL. If a patient with DLBCL is not hardened accordingly, it is oftentimes fatal 5, 14.Furthermore, tumor of follicular lymphoma might relapse and further break up 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 acqu ired through a number of mechanisms, namely genetic transformation of the B-cells. When this occurs, as seen in the case, the give-and-take option will be narrowed down, since chemotherapy is no nightlong an option.15Incidence, Morbidity, and mortality rate RateFollicular lymphomas have an incidence rate of 2500 cases each family in the UK.16 It exhibits the second highest incidence rate among all the lymphomas, with the first creation DLBCL. 17 It dominates 30% of all the NHL and it is the most common type of Low Grade NHL.1, 17Prognosis Index is used to predict the treatment options and outcome of follicular lymphoma. A Follicular Lymphoma Prognosis Index, developed by Solal-Celigny, is currently beingness 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 whic h suffers none of the to a higher placementioned 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 older from 20-34 years old (case scenario patient aged 33years) mortality rate was notwithstanding 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 LymphomaFollicular lymphoma can be considered incurable, but fortunately the growing tumors are sensitive to beam and chemotherapy. Treatment options of lymphomas ar e highly base 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 set in the beginning and patients who were treated according to wait and watch method acting. 20 Treatments options are summarized in table 3.Treatment optionsDescriptionsRadiotherapyUses ionizing ray of light to set aside cellsChemotherapyUses drugs to debar or slow down the growth of cellsmonoclonal antibodyUses proteins that targets rapid growing cellsRadioimmunotherapy hot isotopes combined with monoclonal antibodies osmium Marrow TransplantTransplantation of stem cellsRadiotherapyOne of the ways to treat follicular lymphoma is by acting beam of light, 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 i onizing 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 outdoor(a) beam therapy. 20, 21, 22 External beam therapy is done from a political machine outside the patient, which is known and the linear accelerator. Radiation to body parts preceding(prenominal) 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 patients survival rate will be increased to 83%.23, 24 According to another research by MacManus, 40% of the radiotherapy patient remained disease free later on 10 years.ChemotherapyChemotherapy involves the usage of drugs to stop or slow down the growth of lympho ma B-cells, whence managing the lymphomas symptoms.5, 6 Chemotherapy drugs barely target specific rapid-growing cells such as tumor cells, and impairs their ability to regurgitate 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 gang were proposed, with the common ones being the meat cleaver 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 afterwards a period of 3 years.26 However, a more upstart 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 pharmacopeia 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 TherapyMonoclonal antibody therapy works by using antibodies that sticks to the come to the fore of specific groups of cel ls, such as cancer cells, and trigger the bodys 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 suppo rt therapy, it significantly improves boilers suit 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.RadioimmunotherapyRadioimmunotherapy 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 an d 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 healing(p) portion of the drug. Zevalin is administered via the endovenous 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, conventionly 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 rivulet 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 appraise 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 panelling of radiation and it is being well tolerated by the patient, which was proven in the study.34 In another randomise 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 single 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 supp ression 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 conscionable 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 ScenarioAccording to the patient in the case scenario given, he is currently 33 years-old and he developed chemotherapy resistant advanced follicular lymphoma recently. Advanced follicula r lymphoma indicates that his position 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 elegant 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 operating instructions in NICE guideline. The patient has to be on it for 8 cycles which is somewhat 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 i ncrease both response rate and survival rate as well as improving the long-term prognosis of follicular lymphoma patient. all told 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 junior 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.ConlusionIn conclusion, patient with chemotherapy resistant advanced follicular l ymphoma should be treated with Rituximab, followed by Bexxar and Zevalin. All in all, with the new advances in radioimmunotherapy, the joint crusade 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.