Burkitt's+Lymphoma

This project is going to discuss Burkitt's lymphoma by looking at the disease itself, the mechanism by which it affects the body and the treatment options available for this cancer. We will be looking at two patients and through addressing their case, we will be able to learn more about Burkitt's from an actual patient perspective.
 * Introduction**

Hakim Magoro is a seven year old boy from Mozambique in Sub-Saharan Africa. He lives with his mother, father, and younger sisters in a small rural village. As a young child he was always very healthy but recently contracted malaria. This occurrence is common in Sub-Saharan Africa as mosquitoes carrying the disease prosper in the conditions of high temperature and humidity.
 * Patient Profile **

Hakim’s younger sister Esari, age 5, was in an accident a year ago which required a blood transplant. Since her blood transfusion, her health has declined. She has become much more vulnerable to diseases which she should have been protected against with a healthy immune system. In a follow up visit, she was diagnosed with HIV most likely stemming from the blood transfusion but the exact origins of the disease are not known.

Mr. and Ms. Magoro brought Hakim and Esari to the clinic because of strange growths on their faces. Within the last few days, there has been a lump the size of a golf ball growing on Hakim’s face during the last three weeks. The lump is hard, located on the left side of the face near the lower jaw. They are worried because Esari has begun to show a similar bump on the right side of her face, the size of a large pimple, resembling the initial stages of Hakim’s growth.

Upon examination, the doctor suspected the growth was a tumor. She tested both Esari and Hakim for Epstein-Barr Virus. EBV is an easily transmitted herpes virus, known as the “kissing disease” for its transmission through the exchange of bodily fluids and causing most cases of mononucleosis. In the majority of the population, this virus usually remains latent in B cells without resulting in any major complications. However, in people who are immunocompromised such as those with malaria or HIV/AIDS, EBV can lead to serious complications, including cancer. In this case, both Hakim and Esari tested positive for EBV. The doctor ordered more tests to be sure but she has diagnosed both children with Burkitt’s lymphoma.
 * Diagnosis with Cancer **

Burkitt’s lymphoma is a non-Hodgkin’s form of cancer and is the fastest growing cancer in people. It is an aggressive form of cancer which is most common in children ages 5 to 10. It is also known as small non-cleaved lymphoma, and makes up approximately 40 percent of non-Hodgkin lymphoma cases in the United States but almost 98 percent in Africa.
 * Burkitt’s Lymphoma Profile **

Burkitt’s lymphoma cases are expressed differently depending on the patient population. These differences are seen in geographical region, gender and race. In Africa, Burkitt’s lymphoma makes up almost all non-Hodgkin lymphomas cases and more than half of all cancer cases diagnosed in children. In these cases, the lymphoma usually develops in the jaw and facial bones as seen in Figure 1 above. In the United States, Burkitt’s lymphoma is mostly seen beginning in the abdomen as seen in Figure 2 below. This tumor can grow and block bowel movements causing complications such as pain and vomiting. This cancer is also more common in Caucasians than those of African descent and twice more common in boys than girls.

Due to the nature of the disease, it is important to treat Burkitt’s lymphomas quickly. Not only does it grow rapidly, it can spread to other parts of the body such as in or near the brain. The fact that this cancer affects the B cells in the immune system would explain why this cancer is mostly present in people with weakened immune systems such as those with HIV/ AIDS, infected with malaria, diagnosed with congenital defects or on immune suppression drugs after an organ transplant. Normally the immune system can resist attack but with an immunocompromised system the B cells, especially when associated with EBV, can live longer and accumulate more mutations. This also can explain why the cancer grows so quickly. As part of the immune system, B cells are all over the body and are made to attack an infection or danger. Tumors of Burkitt’s lymphomas are usually clumps of B cells which is characteristic of B cells going towards the site of an infection or potential danger. In this case though it causes more harmful effects than positive ones as it allows B cells to form a solid mass. To really understand how this cancer works however, the basics of cancer need to be understood and the molecular mechanism needs to be discussed.

**Hallmarks of Cancer** When many people think of cancer, they think of chemotherapy and treatments but rarely does anyone focus on the molecular basis of the cancer. The biology of the cancer cells and tumors can be critical in providing treatment to the affected patient. Cancer is characterized by a series of hallmarks and defining properties that can be used to understand the disease on a deeper level. The hallmarks of cancer as defined by Hanahan and Wineberg are: sustaining proliferative signaling (can continuously tell itself to divide and grow), enabling replicative immortality (can divide forever), evading growth suppressors (divides without limits), activating metastasis (can spread to other parts of the body), inducing angiogenesis (can get nutrients), and resisting cell death (can avoid cell suicide). Emerging hallmarks include: genome instability (promote mutations), promoting inflammation, evading immune destruction and reprogramming metabolism. All cancers have at least one of the hallmarks previously mentioned, many of which display multiple hallmarks. Burkitt’s lymphoma is characterized by the expression of the c-MYC gene. Genetically, tumors in Burkitt’s lymphoma occur when the cells experience a translocation between chromosomes 8 and 14 in 75 to 85% of the time, 8 and 22 in 10% of the time, 8 and 2 in 5% of cases. There are also cases where there is a three way translocation between a mix of the chromosomes. This translocation is present in both the endemic and non-endemic types.Translocation cuts and staples pieces of different chromosomes together that should not really be mixed. In this instance, the c-MYC gene is placed next to a promoter region, increasing the expression of the gene. Constitutive expression of c-MYC induces proliferation even in the absence of growth factors, playing a role in cell growth and differentiation. Systemic treatment needs to control cell growth and proliferation which can be regulated with drugs such as Methotrexate and Vincristine. However, a few scientists have seen the potential to use this translocation as a target for specific therapy. Although none are actually on the market right now, a promising project seems to be using specific T-cells to attack oncogenic cells with a c-MYC mutation and isolating this somehow to make a vaccine to treat Burkitt’s lymphoma. Many cases of Burkitt’s lymphoma also show a loss of function change in p53. This gene acts as a security guard. It detects mutations and issues in the cell and either stops the cell cycle to give it time to be fixed of triggers death of the cell if the damage is too extensive. In a mutated p53 version, there is no security guard to stop the chaos in the cell. This is how cancer cells evade apoptosis and is one of the hallmarks. Looking at the chemotherapy options, drugs like Doxorubicin and Cyclophosphamide help the cell because they can trigger apoptosis through a different mechanism, making up for the loss of function of p53, making this treatment effective. Now that the molecular basis is understood, the next step is to understand the tests used in identifying and the procedures used in treating Burkitt’s lymphoma.

**Medical Diagnosis** This cancer is often preliminarily diagnosed through a checkup of the tumor. Usually the size and placement will give an indication that it is Burkitt’s. Once there is the suspicion, clinical exams need to be conducted. The exams include: biopsy of a piece of the tumor, a CT scan, a chest X-ray, a PET scan, a bone marrow biopsy, examination of the spinal fluid, blood tests to measure kidney and liver function and testing for immunocompromising diseases such as HIV. For Hakim, his diagnosis was confirmed with a biopsy of tissue from the tumor on his face. For Esari, confirmation of her status with HIV and a biopsy of the tumor also confirmed the diagnosis. Now, they must both undergo specified treatment.

**Standard of Care** Burkitt’s lymphoma is usually treated with several sessions of chemotherapy, even if it is in a localized early stage. Intensive intravenous chemotherapy has the best chance of being the most effective and needs to be performed as an inpatient procedure because some of the drugs take several hours to administer over a period of days. In addition, this will require constant replenishment of fluid with an IV drip. It is also important to be treated at an inpatient center because the patient will require monitoring through blood tests to check liver/ kidney function and blood cell count.

On a molecular level, treatments for this cancer need to target fast dividing cells like B cells which accumulate to form the tumors. Chemotherapy targets normal cells as well as cancerous cells because it targets cells which grow and divide at a fast pace. B cells grow very fast in comparison to other cell types and are therefore preferentially attacked in Burkitt’s. However, this has its own implications as B cells are part of the immune system. This cancer affects people who have a weakened immune system already so to further debilitate them is a serious downside of traditional chemotherapy treatments.

Treatment that targets the brain and spinal cord called Intrathecal Chemotherapy is also needed when treating Burkitt’s lymphoma. This involves injecting chemotherapy drugs, most often methotrexate and cytarabine, directly into the cerebrospinal fluid. Methotrexate is an oral tablet usually given to treat rheumatoid arthritis, severe psoriasis and some types of cancers including lymphomas. It works by slowing down the growth of cancer cells. Cytarabine is a powder which, when combined with liquid, can be injected intravenously. This drug works in a similar way as methotrexate as it also slows down the rate at which cancer cells grow.

Usually the desired treatment is administered through a lumbar puncture but sometimes Ommaya Reservoir is put in place to prevent constant lumbar punctures. An Ommaya Reservoir is a quarter sized dome attached to a catheter which is inserted under the scalp and placed in the brain. It is used to mainly test the cerebrospinal fluid for cancer cells and to give medication such as chemotherapy directly to the cerebrospinal fluid. There are many regimens and combinations depending on the overall health of the patient, cancer stage and age. Common drugs include: cyclophosphamide, cytarabine, doxorubicin, etoposide, methotrexate and vincristine. All of these drugs are prescribed because they slow down or stop growth of cancer cells in the body.

For children and adolescents, two cycles of COPADM is usually recommended: Cyclophosphamide, Vincristine, Prednisolone, Doxorubicin, and Methotrexate. This is followed by other chemotherapy regimens such as a combination of cytarabine and methotrexate. If these are ineffective, other means of treatment include: stem cell transplant, radiation therapy, steroid therapy or Rituximab (a monoclonal antibody that sticks to cancer cells and triggers the immune system) which is usually just given to adults.

Specific Treatment of Burkitt’s lymphoma For the COPADM treatment plan, each medicine focuses halting a different mechanism in the cancer cells. Cyclophosphamide triggers apoptosis, a mechanism to tell the cell that it needs to self-destruct. It adds an alkyl group to the guanine base of DNA in lymphocytes. This interferes with DNA replication and ultimately leads to cell death.

Vincristine works by arresting the cell in the metaphase stage of mitosis. In this phase, the chromosomes line up at the metaphase plate and get ready to separate. Vincristine interferes with tubulin, making it so the chromosomes cannot split apart or finish the cell cycle. In addition to this mechanism, Vincristine also affects cellular respiration and the synthesis of nucleic acids.

Prednisolone causes an increase or decrease in expression of specific target genes by binding to a DNA receptor and interacting with transcription factors. As a glucocorticoid, prednisolone also acts as an anti-inflammatory agent by limiting capillary dilatation and restricting the accumulation of macrophages.

Doxorubicin inhibits macromolecular synthesis. It also forms complexes with DNA by squeezing in between base pairs. It inhibits topoisomerase II activity, preventing relegation. This means that topoisomerase cannot fix tangles in the DNA because it cannot put back together the double stand cuts that it makes in the DNA. This hurts the cell and can lead to apoptosis.

Lastly, methotrexate inhibits the synthesis of DNA and RNA, interfering with replication and proliferation of the cell. This drug inhibits folic acid reductase, which converts dihydrofolate to tetrahydrofolate. Tetrahydrofolate is essential in the de novo synthesis of purines and some amino acids. In other words, it prevents the synthesis of some of the bases, leading to the inability to replicate the genome and therefore for the cell to proliferate and grow.

Treatments are usually given in conjunction with preventative antifungals and antibiotics. Treatments also include anti-sickness drugs and growth factors to promote regeneration of bone marrow. Short term side effects include: neutropenia (low white blood cell count making one more prone to infections), anemia (making one short of breath and very tired), low platelets concentration (may need platelets transfusions), sore mouth or mouth ulcers, feeling sick and nauseated or having diarrhea, temporary hair loss, fatigue, peripheral neuropathy (damages to nerves especially in hands and feet). Long term side effects include: reduced fertility, increased risk in secondary tumors and development of a second cancer and heart disease.

**Follow Up Treatment:** In most cases, the cancer ends with complete remission. For the first few check ups, the patient will have an appointment every month. After a few months, if everything goes well, the appointments spread out to every 6 months over a few years. If the cancer comes back, then the doctor can offer other treatments such as a higher dose of chemotherapy or undergo a stem cell transplant once the lymphoma has responded again to chemotherapy.

**How effective are current treatments?** Burkitt’s lymphoma is fatal if left untreated. In children, prompt intensive chemotherapy usually cures Burkitt lymphoma, leading to long-term survival rates of 60 to 90 percent. In adult patients, results are more variable. Overall, prompt treatment is associated with long-term survival rates of 70 to 80 percent.

**Clinical Trials** For some patients who want to try different routes of treatment, participating in a clinical trial can be an option. This involves being a participant in a study that is either trying to gather information or is testing out an experimental treatment. When looking over government approved clinical trials, 718 total trials came up for Burkitt’s lymphoma. These each had a different status: terminated with results, completed, unknown and recruiting. Of those, 103 clinical trials are currently recruiting patients with Burkitt’s lymphoma.

While searching through each, five studies really stood out. The first, Phase II Study of Dose-Adjusted EPOCH-Rituximab in Adults With Untreated Burkitt Lymphoma and c-MYC+ Diffuse Large B-Cell Lymphoma seemed promising as it is a trial testing a new treatment to make chemotherapy less toxic. However, this study was restricted to participants 18 years and older, making them inelegible. The second one, Short Term Intensified Chemo-immunotherapy in HIV-positive Patients With Burkitt Lymphoma (CARMEN) again is for adults of legal age. The third study, Epidemiology of Burkitt Lymphoma in East Africa Children or Minors (EMBLEM) is a study both Esari and Hakim qualify for but this study is only studying the epidemiology of Burkitt’s lymphoma. This is a very important field to study and gives lots of helpful data, but it is not very helpful to Hakim and Esari as it gives not even a chance at an experimental treatment.

The last two studies, Burkitt Leukemia - Dose-Adjusted Etoposide, Prednisone,Vincristine, Cyclophosphamide, and Ofatumumab (EPOCH - O)and Dose Adjusted EPOCH-R, to Treat Mature B Cell Malignancies (DA-EPOCH-R) are intervention clinical trials which do offer the possibility of being injected with an experimental treatment that could potentially work. However, for the DA-EPOCH-R study, patients with HIV are not allowed in the treatment. Looking at all this data just from these five cases, I would not recommend a clinical trial for Hakim and Esari for reasons that will be explained shortly. However, if they had to be assigned just one to be required to participate in, the doctor should recommend Esari try to join the DA-EPOCH-O trial as she qualifies and it is a form of intervention to help with her cancer. Hakim could either join the DA-EPOCH-O or DA-EPOCH-R trials. He qualifies for both studies and they both offer interventions for his cancer. However, the scientists conducting the clinical trials might not want family members in the study so for those reasons he might have to be in a different clinical trial than Esari.

**Recommended Treatment** As for practically thinking of prescribing treatment, it would be difficult to treat Hakim and Esari. First of all, taking into consideration the socioeconomic aspects of the case, their treatment options are already limited. Hakim and Esari come from a low income family in a village far from larger cities. There are not many health centers near to where they live. Those that are the nearest are either not of great quality or are of great quality but do not have the necessary resources to treat this type of cancer. Care centers with the necessary resources are often closer to larger cities so that would make it difficult for their parents as their mom and dad work long hours during the day in order to provide food for their kids. Financing treatment for Hakim and Esari’s cancer is also a huge concern. They do not have a lot of money to pay for the continuous hospital stays that cancer treatments usually require, transportation to and from the inpatient center, and do not have means of making more money at the moment. This makes it difficult for the family but also needs to be taken into consideration for the doctor prescribing treatment.

Taking their socioeconomic situation into account, the best idea for treatment would be to prescribe them chemotherapy and not enlist them in a clinical trial yet. Chemotherapy seems to be effective in adolescents with Burkitt’s lymphoma. Both children do not have seriously advanced forms of Burkitt’s lymphoma. Esari’s lymphoma is barely developing into a tumor and Hakim’s, while a tumor, has remained localized on his face and has not spread to the brain or abdomen. Esari does have HIV making chemotherapy more dangerous as her immune system is weak and the treatment will only make it more susceptible to infections. However, her condition can be better treated in a hospital setting where her individual treatment is the main goal. As stated previously, there are a few clinical trials she qualifies for. However, prospects for her seem to be better with direct chemotherapy treatment. Hakim, while was infected with malaria, is healthier and would seem to benefit from chemotherapy. This can be a dangerous move though because in the chance that chemotherapy does not work, having had prior clinical treatment does disqualify both children from many clinical trials.

Overall, I would recommend intensive intravenous therapy for Hakim and Esari. Steroid therapy and stem cell transplants are reserved for people who have more advanced cases of cancer. Especially since Esari has HIV, she is not very healthy and her immune system cannot take extensive chemotherapy. Intravenous therapy seems like the best option because it is the most practical. It is the most widespread treatment for this disease and has set guidelines for general treatment plans depending on each patient’s case. This intravenous therapy would probably be compromised of cytarabine, methotrexate and some type of antifungal/ antibacterial treatment for each child along with chemotherapy injected directly into the cerebral spinal fluid. I would not give Esari Rituximab as it works by triggering immune cells and relying on the immune system to fight the cancer. This would be a detrimental treatment for her as her immune system is not strong enough to handle those demands. Hakim is in a similar boat. He was infected with malaria and has a temporarily weakened immune system which would not work well with Rituximab. I suggest he get a higher dose of the chemotherapy than Esari and have more back to back Intrathecal chemotherapy treatments as he has a more developed form of Burkitt’s. However, it is the doctor's decision.**

The doctor at the clinic recommends the COPADM treatment plan. It is mostly used for adolescents and has shown good results in achieving remission of the cancer. However, as a clinic, they do not have the right tools to provide chemotherapy. Having known this family for a long time, she contacted St. Mary’s Hospital in Lacor, Uganda. This hospital is known for giving subsidized care for cancer patients. Back in 2010, they had large numbers of patients who still could not afford treatment despite the low costs. In response to this, they set up a fund where donors could fund a patient in order for them to get treatment. She sent in an application for Hakim and Esari. A few days later, she received word that two anonymous donors had agreed to fund the children’s care. In addition to this, the foundation also helps families find subsidized housing for at least a year while the child, in this case children, undergoes treatment. When presented this news, Hakim and Esari’s parents were critical of this news. They did not want to venture out into a place almost 1,500 miles away and did not see how they could leave their jobs. However, they understood their situation and opportunity that they were being offered. They have decided to take Hakim and Esari to Uganda for their treatment, they leave within in a week.

As the doctor speaks to the parents, she says, "I know you are scared. I know you are worried and do not want to leave the area. But the care your kids require is not here. You will be in good hands at the hospital. Make sure they explain everything to you. If they don't, make sure to ask. You are the parents. Doctors are meant to bridge the gap between medical science and the patient, they are not meant to decide everything on their own. If you need my help, just contact me. The best option is the COPADM treatment plan but if that does not work do not worry, there are many other options like radiation therapy and clinical trials.

Burkitt's is strong, but with the right treatment 80% survive. As a unit, we are stronger than Burkitt's, don't forget it."

This is the link to St. Mary's Hospital Lacor in Uganda. You don't need to be a doctor to make an impact. []