Part I: The Cancer



Lauren is a six-year-old white female from the San Francisco Bay Area. She lives with her father, a technology executive, her mother, an art teacher, and her younger brother. For the past couple weeks, Lauren has been unusually lethargic and presents small swollen lumps around her neck. Lauren’s mother suspects a virus such as mononucleosis and brings Lauren to her pediatrician. Because her symptoms are mild, the pediatrician also suspects a virus and advises Lauren to rest. Several days later, her parents notice bruising on Lauren’s arm that does not heal. She also begins to complain about pain in her legs and the upper left area of her abdomen. She returns to her pediatrician who immediately suspects leukemia. Lauren is referred to UCSF Medical Center. After further testing (detailed below), Lauren is admitted to the Pediatric Oncology Unit and diagnosed with acute lymphocytic leukemia (ALL).

Acute lymphocytic leukemia is the most common form of childhood cancer, making up 30% of all cases (1). It is estimated that in 2016, there will be around 6,600 new cases of ALL in the United States (2). ALL is a cancer of the blood and bone marrow, which specifically affects white blood cells also known as lymphocytes. In a healthy child, blood stem cells are produced in the bone marrow where they become either a myeloid stem cell, or a lymphoid stem cell. Lymphoid stem cells are specifically responsible for producing immature lymphoblasts, which give rise to mature lymphocytes. These can be either T-cell or B-cell lymphocytes (3). In a child like Lauren with ALL, too many blood stem cells develop into lymphoid stem cells. Consequently, an excess of immature lymphoblasts and lymphocytes are produced and accumulate within the blood. These immature cells are the cancer cells (Loc. cit.).

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Figure 1. Anatomy of the Bone Marrow
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Figure 2. Blood Cell Development

There are a few known risk factors associated with the development of ALL. Past treatment with chemotherapy or exposure to radiation increases the chance of getting the disease. Chromosomal and genetic abnormalities such as Down Syndrome or Klinefelter Syndrome or specific chromosomal translocations can also raise the risk. Finally, exposure to certain chemicals such as benzene has been linked to ALL (4). Benzene is a common ingredient in certain art supplies and paint strippers. In Lauren’s case, she might have been exposed to the benzene in her mother’s art materials, increasing her risk for ALL.

Despite receiving a diagnosis, the scope of Lauren’s disease can be narrowed. Upon admittance, a complete blood cell count (CBC) was performed. Analysis of Lauren’s blood reveals that she has a white blood cell count of over 32,000 cells per microliter. A healthy child will have a count between 5,000 to 10, 000 cells per microliter (5). A spinal tap is also performed to check for cancer cells in Lauren’s cerebrospinal fluid. Testing concluded that Lauren’s cancer had not spread to her brain or spinal cord. A bone marrow biopsy may also be done to count the number of and look for changes within the cancer cell chromosomes (3). Using the bone marrow, cytogenetic analysis looks for changes in the chromosomes within Lauren’s lymphocytes. The analysis reveals Lauren has a translocation between chromosomes 12 and 21, giving her a higher chance of being cured (6). This is because the translocation is associated with signal transmission deregulation and transcription factor deregulation (7). Another test called immunophenotyping checks the antigens on Lauren’s cancer cells to see if they are B-cell or T-cell lymphocytes (3). The testing confirms that Lauren has the T-cell sub-type. In other words, she has a build up of T-cell lymphocytes. Being placed in this sub-group neither increases nor decreases her chances of recovery. It does however affect the exact drugs she will be given. This array of diagnostic factors places her in a standard-risk group (8). This risk group classification will affect her subsequent course of treatment.

With the knowledge of Lauren’s high white blood cell count, her symptoms can be further interpreted. The overgrowth of the lymphocytes leaves little room for healthy blood cells including red blood cells and platelets (1). Few healthy cells are left to transport oxygen and adequately fight off infection. The stress on the immune system and lack of oxygenation to the muscles results in fatigue. Additionally, the leukemia cells may build up in various areas of the body. A build up of cancerous cells in the bones, joints, and spleen are likely the cause of Lauren’s abdominal and leg pain (3). Build up within the lymph nodes is likely the source of the small lumps on Lauren’s neck. Furthermore, the bruising on Lauren’s arms is ascribable to the deficiency of platelets in her blood. Without sufficient platelets, Lauren’s bleeding is unable to be adequately clotted and repaired (9).

Lauren’s chances of recovery are high. Survival rates of acute lymphocytic leukemia are over 90% (10). The cancer has not spread to her brain or spinal cord and her blood counts keep her in the standard-risk rather than the high-risk group. The localization of the cancer within the blood and bone marrow means that Lauren is likely in an early stage of the disease. Her cancer cells also possess a chromosomal abnormality that is associated with higher cure rates (6). Although the first two weeks of treatment are the most important in determining a prognosis, Lauren initially has a high likelihood of recovery.


Part II: The Molecular Basis



All cancers, including Lauren’s, develop as a result of mutations leading to uncontrolled cell growth. A series of mutations within Lauren’s cells have lead to her T-cell acute lymphocytic leukemia (T-ALL). Hundreds of genes and factors are involved in the development and proliferation of T-ALL. However, the most prevalent of these: CDKN2A, NOTCH1, TAL1, and LMO2 lead to a “malignant transformation” within the cells giving rise to T-cells, called T-cell progenitors (11). This is a multistep process that affects cell growth, proliferation, survival, and differentiation (11).

The most common individual mutation in T cell progenitors is the “deletion of the CDKN2A locus in chromosome band 9p21” (11). Over 70% of all individuals with T-ALL possess this mutation. Within the CDKN2A locus are two tumor suppressor genes, p16/INK4A and p14/ARF (11). The deletion of the CDKN2A locus in T-ALL patients also deletes the p16/INK4A and p14/ARF factors suppressing tumor growth. In Lauren, this means the lymphocytes and lymphoblasts continuously multiply, leaving the bone marrow before they are fully mature (3). The cells are insensitive to anti-growth signals, one of the six original hallmarks of cancer.

Individuals with T-ALL frequently exhibit translocation and abnormal “expression of transcription factor oncogenes” (11). This translocation or rearrangement of chromosomes results in overactive expression of factors that increase cell replication. One of these factors is TAL1, a transcription factor that leads to the promotion of cell growth. However, the transcriptional programs of this oncogene are mostly unknown (24). Overexpression of TAL1 is “present in approximately 60% of T-ALL cases” (11). This overexpression is caused by rearrangement in chromosome band 1p32 causing TAL1 to be controlled by an unknown neighboring cell growth promoter (11). Consequently, the cancer cells are able to proliferate. A second transcription factor, LMO2, also leads to the promotion of cell growth. Abnormal expression of LMO2 is present in “45% of all T-ALL cases” (11). The presence of both TAL1 and LMO2 oncogenes is possible and its effects and prognosis have been studied in mice (25). The mechanisms of LMO2 activation are largely unknown. However, LMO2 and TAL1 can form transcriptional complexes, which promote cancer cell transcription and therefore, proliferative cell growth.

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Figure 3. NOTCH1 signaling pathway
Furthermore, the activation of a signaling pathway called NOTCH1 is commonly observed in T-ALL affected individuals (11). This pathway regulates normal T-cell development but when mutated is the most prominent tumor-causing pathway in T cell transformation (11). NOTCH1 is activated when molecules bind to a subunit causing a cascade reaction (16). The last reaction in the chain is catalyzed by an enzyme called γ-secretase, and generates intracellular NOTCH. The intracellular NOTCH is then transported to the nucleus and “forms a large transcriptional activation complex”, effectively activating the pathway (16). Mutations that enhance activity occur within the protein and a sequence of amino acids (proline, glutamic acid, serine, and threonine) (16). Each of these factors works to regulate cell destruction (16). Furthermore, a mutated NOTCH1 pathway works to inhibit p53 (12). Functional p53 “is a transcription factor that functions by inhibiting cell-cycle progression or inducing apoptosis in response to cellular stress or DNA damage to maintain genome integrity” (12). The inhibition of p53 leads to infinite replication and lack of destruction despite DNA corruption (another hallmark of cancer). The cells containing damage are allowed to give rise to infinitely more cells. This build up of damaged cells is Lauren’s cancer.

Genomic testing can allow Lauren’s doctors to determine what, if any, of the above mutations are present in Lauren’s cancer cells. This knowledge will help them tailor Lauren’s treatment plan to her specific cells.


Part III: Treatment and Outcomes



The standard course of treatment for T-cell acute lymphocytic leukemia is split into three phases.
The first phase is called remission induction. The goal of this phase is to kill close to 99.9% of the leukemia cells and send the patient into remission (17). However, this still leaves about 100 million cancer cells in the body (18). Therefore, further treatment is still required. The second phase, consolidation or intensification, attempts to “kill any leukemia cells that remain in the body” (17). This means that the treatment is intensified with stronger dosages. The third and final phase is maintenance. The patient continues lower doses of their previous treatment in order to continue “killing any remaining leukemia cells that may regrow and cause relapse” (17). The maintenance phase typically lasts about two years (18). By continuing the therapy after remission, doctors are working to prevent a relapse, which has much lower rates of survival (17).

Throughout these phases, two standard types of treatment are used. The intensity of the treatment depends on the risk group the patient has been placed in (18). A more intensified treatment may involve higher dosages of drugs, more rounds of the drug therapy, and riskier treatment (such as brain radiation). Lauren is in the standard risk group and therefore will receive less intense treatment.

The first treatment type, chemotherapy, is administered. Standard risk patients are given “L- asparaginase, vincristine, and a steroid drug (usually dexamethasone)” (18). L-asparaginase “breaks down the amino acid asparagine and may block the growth of tumor cells that need asparagine to grow” (19). Vincristine interferes with mitosis by "preventing the formation of the mitotic spindle" leading to the death of the cancer cell during metaphase of the cell cycle (20). In Lauren’s case, the chemotherapy is injected into the blood or muscle, allowing the drugs to travel through the bloodstream and kill cancer cells throughout the body (17). The steroid drug is administered to counteract the side effects of the other drugs such as nausea, loss of appetite, and inflammation (22). Additionally, a third chemotherapy drug, methotrexate, is administered though a spinal tap in order to “to kill any leukemia cells that might have spread to the brain and spinal cord” (18). Methotrexate inhibits the synthesis of DNA and RNA, which halts cell growth and replication (21). The combination chemotherapy kills leukemia cells throughout Lauren’s body before she continues treatment.

The second type of treatment, radiation therapy, uses high-energy radiation to “kill cancer cells or keep them from growing” further (17). However, radiation treatment to the brain has side effects, especially for young children. It can “cause problems with thinking, growth, and development” and may also affect the child’s mood and future temperament (18). However, in Lauren’s case, the cancer has not spread to the central nervous system and her chemotherapy regimen is intense enough that she does not require brain radiation. Instead, the radiation will be administered to areas of cancer cell build up such as her bruised arm. The radiation therapy works to kill off leukemia cells left behind by the chemotherapy.

Combination chemotherapy is the most common treatment for T-ALL patients but targeted therapies are being actively studied in clinical trials (15). These therapies target the mutations within Lauren’s cancer cells. One of these targeted therapies, gamma-secretase inhibitors, targets the NOTCH1 pathway in order to obstruct it (13). Gamma-secretase, which generates NOTCH, is inhibited and therefore, does not allow the mechanism to continue. By hindering the mutated pathway, the cell survival and apoptosis resistance in the cancer cells is also inhibited. In other words, the cancer cells can be destroyed (13). However, efficacy statistics of this treatment have not yet been released. Another targeted treatment drug, nelarabine, is toxic to the actual T-cells, allowing them to be exclusively targeted and killed (14). Trials of nelarabine show 47-55% response (both complete and partial remission) in pediatric T-ALL patients (23). This is encouraging for those patients who relapsed after standard chemotherapy. These targeted therapies are a promising new treatment option for T-ALL patients.

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Figure 4. Gamma-secretase inhibitor within cell


Lauren has two choices for treatment: a standard therapy or a targeted therapy through a clinical trial. Using the standard course of treatment has resulted in complete remission rates of 95-100% and disease free survival rates of 80-85% in pediatric patients (22). In contrast, only 23% of patients on nelarabine have achieved complete remission (23). The side effects of the targeted treatments are also more severe and include ataxia (loss of full control of bodily movements), confusion, and other forms of neurotoxicity (23). Lauren is a standard risk, newly diagnosed T-ALL patient. Therefore, a standard course of treatment with chemotherapy and radiation is her best treatment option. If she were a high-risk or relapsed patient, a targeted therapy may provide higher chances of survival. However, a standard treatment plan balances the higher complete remission rates with less severe side effects.


Conclusion



Despite being diagnosed with a notoriously aggressive disease, Lauren has a hopeful prognosis. This is her first battle with leukemia and her chances of complete remission are extremely high. Standard chemotherapy and radiation are excellent treatment options. Furthermore, targeted therapies are being actively studied should she ever relapse. With successful treatment, Lauren can resume a normal childhood and put her battle with cancer behind her.


Apercu



Once considered a death sentence, pediatric acute lymphocytic leukemia has become one of the more treatable cancers. With continued scientific investigation, the prognosis for leukemia patients like Lauren can only improve.



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