A Case of Childhood Acute Lymphoblastic Leukemia

Part I
Grace is a 6 year-old, white female whose parents checked her into O’Connor Hospital today after she woke with a high fever, experiencing severe pain. Over the past month Grace has been lethargic, despite sleeping more frequently, and her appetite has decreased substantially. Grace’s parents initially suspected a seasonal cold or flu given she began school this year and as a result, has had direct exposure to many viruses going around. However, they became more suspicious when their daughter continued to complain about aches in her body and they found a lump in her underarm while helping her get dressed.

In the initial consult, the physician could clearly see Grace’s condition was more complex than a flu and transferred her to a pediatric oncologist for further examination. There, the pediatric oncologist evaluates Grace’s physical state and finds petechiae, or red spots, on the skin as well as excessive bruising and the swollen glands in her underarms.[1] [2] From these symptoms alone she determines that Grace has likely fallen victim to childhood leukemia.

Leukemia is the most prevalent form of cancer in children, accounting for every 1 in 3 cancer cases in child patients. There are two main forms of leukemia in children, acute lymphoblastic leukemia and acute myeloid leukemia. The oncologist might suspect acute lymphoblastic leukemia, as it accounts for 75% of all childhood leukemia cases. Further, within acute lymphoblastic leukemia there are four subcategories: Early Pre-B cell, Pre-B Cell, Mature B cell, and T cell.[3]

Figure 1: Blood Stem Cell Development
The oncologist explains her suspicions to Grace’s parents and elucidates what this means for their daughter by giving a brief biological overview of the processes affected by leukemia. In a normal, healthy individual, the bone marrow makes blood stem cells that become mature cells over time. These cells become myeloid stem cells or lymphoid stem cells and develop as seen in Figure 1. Both B and T lymphocytes make antibodies to fight infection, whereas the killer cells discretely target cancer cells and viruses.

In a child with acute lymphoblastic leukemia, too many blood stem cells become lymphoids and give rise to immature lymphoblasts. These stem cells replicate, unregulated, creating a large number of immature lymphoblasts in the bone marrow, which crowd out the normal, healthy cells. This leads to infection, anemia, and easy bleeding, as the white blood cells, red blood cells, and platelets can no longer function at their normal capacity. [4]

To confirm this is Grace’s illness, blood chemistry studies will have to be done on blood samples taken from Grace, as well as a complete blood count done on the blood sample to gauge the severity of her leukemia. Other tests the oncologist would likely perform to understand Grace’s leukemia better include a Lumbar puncture, a chest x-ray, and a bone marrow aspiration and biopsy. The lumbar puncture will check to see if the cancer cells have spread to Grace’s cerebrospinal fluid. This test involves sticking a needle into the patient’s spinal column and withdrawing the fluid (Refer to Figure 2). A chest x-ray will help the doctor determine if the cells have spread and formed a mass in the chest of the patient. Lastly, a bone marrow aspiration and biopsy will allow the oncologist to perform a cytogenetic analysis on the bone marrow or blood and see if there are any changes in chromosomes or genes. This is done by inserting a hollow needle into the hip bone or breast bone of the patient and removing a sample of the bone marrow.[5]

If the oncologist’s assumption is correct and Grace has acute lymphoblastic leukemia she can further categorize her illness. Within the scope of acute lymphoblastic leukemia, a patient is usually labeled as low-risk or high-risk. These classifications are based off multiple criteria including age, white blood cell count at the time of the diagnosis, immediate response to treatment, whether leukemia cells are found in the cerebrospinal fluid, and whether any genes or chromosomes have been mutated. A child within the age range of 1-9 is usually considered low risk, ignoring other factors, while a child under 1 or older than 10 is usually categorized as high risk. This is because children generally between ages 1 and 9 tend to have certain cytogenetic traits, like hyperdiploidy- more than the normal diploid number of chromosomes- making treatment more beneficial. Also a white blood cell count greater than 50,000 cells per microliter is considered high risk, as this is higher than an average 10,000 cells per microliter inferring there is a large accumulation of these lymphoblasts, crowding out the all of the healthy blood cells. Further, the sub-type of the leukemia also plays a role, as children with Early Pre-B cell or Pre-B cell acute lymphoblastic leukemia have a better outlook as the leukemia cells are not as mature and developed. Lastly, if the leukemia cells have spread to the cerebrospinal fluid, the child is automatically placed in the high-risk category, as this means the cancer has metastasized to the central nervous system.[6] [7]

The prognosis for a child with acute lymphoblastic leukemia is a lot more positive than for an adult. If Grace does have acute lymphoblastic leukemia it can likely be cured, as the current 5-year survival rate is 85 percent. The odds of course vary depending on when treatment was given in the cancer’s development, characteristics of the patient, whether they were high or low risk, and their individual response to treatment. Despite the treatment of acute lymphoblastic leukemia being very successful, the damage resulting from radiation treatment and chemotherapy largely increases the child’s risk for developing other types of cancer within their lifetime. If Grace enters the maintenance stage in treatment of the leukemia, it is important she be monitored closely for new cancer symptoms or a possible relapse.[8] Before discussing these later stages, however, they must first start Grace on some sort of treatment, which will be best determined after her blood tests and lumbar puncture are performed.

Part II
Upon analyzing Grace’s blood work, the oncologist is able to confirm she has acute lymphoblastic leukemia originating from the B cells. There were no cancer cells detected in her cerebrospinal fluid, meaning Grace is negative for CNS disease. Further, cytogenetic analysis also reveals Grace is negative for the Philadelphia chromosome, translocation or rearrangements of chromosomes 9 and 22 common in adult patients. Now that the oncologist understands Grace’s individual case, she categorizes her as a low risk patient for moving forward in her treatment.

To start formulating a treatment plan for Grace’s leukemia, she sits down with her parents to discuss first the general treatment procedures. There are three phases in the cancer treatment, induction, consolidation/intensification, and maintenance. In the induction phase, the aim is to kill as many leukemia cells as possible. This phase, if all goes as planned, should last about a month. During this phase, Grace will be hospitalized for long period of time, as she will have a high risk of infection. This is because the chemotherapy drugs will attack her normal, healthy cells as well as the cancer cells, severely weakening her immune system. After induction, the oncologist will assess if Grace has high levels of MRD, minimal residual disease, or little to no MRD. Minimal residual disease is the name given to the small number of cancer cells remaining in the bone marrow, not detectable by microscope, after the induction phase. These cells are targeted during the second phase, as they are the central cause for relapse of the leukemia. If after remission, when all cancer symptoms have subsided, there are residual leukemia cells, then Grace will be classified as high risk and put on a higher dosage of chemotherapy drugs in an intensification phase. If there is no MRD, seen in about 75% of cases, then Grace will remain low risk.[9] She then will not need to be given high doses during consolidation, as this would likely have a negative effect on Grace’s prognosis in the long term due to damage from the chemotherapy drugs. Finally, the maintenance phase will likely last a few years after Grace is in remission completely from the consolidation/intensification phase. She will be monitored continuously to ensure the cancer remains in remission and no new symptoms arise.

During these phases patients are treated with some variation of these four forms of leukemia treatment: chemotherapy drugs, radiation, stem cell transplants, and targeted therapy. Chemotherapy is always the main method of treatment, as will be the case for Grace. During chemotherapy, anti-cancer drugs are implemented into the patient in the form of a pill or intravenously. If delivered intravenously, it is common to insert a catheter into the patient for anywhere from a few weeks to a few months, to avoid having to insert a needle numerous times into the patient's vein. For chemotherapy, a combination regimen is commonly prescribed, including multiple anti-cancer drugs along with corticosteroids to regulate inflammation and assist the body in recovering from many side effects of the drugs.[10]

For Grace, the drugs the oncologist prescribes will be L-asparaginase and Vincristine, with a corticosteroid such as Dexamethasone, one of the most common drug combinations for childhood leukemia due to the high levels of remission it leads to in low risk patients. Both drugs will be injected intravenously. Vincristine slows and eventually stops the growth of cancer cells through it's ability to disrupt the formation of mictrotubles at the mitotic spindle. This prevents mitosis, or cell division, from occurring. [11] Stopping mitosis would greatly affect the rapidly dividing cancer cells as they are constantly entering this process, however it would also kill many of our healthy cells, which have fast turnover rates. L-asparaginase kills or stops the growth of cancer cells by breaking down asparagine, an essential chemical in cells, to aspartic acid and ammonia. Normal cells can produce asparagine for themselves, but cancer cells cannot, leading to their greater rate of cell death over normal, healthy cells.[12]

Figure 2: Lumbar Puncture diagram

Because Grace is a young patient and can handle a more intense treatment, as opposed to adult patients, the dosage of her chemotherapy will be high initially. The high doses do pose risks to Grace's health in the long term, however, if all goes to planned the drugs will kick in fast and eliminate the cancer within the first month, so she will not need them in the second phase of treatment. The chemotherapy drugs will have a range of side effects, which varying from patient to patient, including nausea and vomiting, hair loss, fatigue, easy bruising and bleeding, mouth sores, numbness of hands and/or feet, diarrhea, lack of appetite, and problems with blood clotting. [13]
As previously stated, risk of infection will be much higher during the treatment, so she will need to hospitalized during portions of her first round of chemotherapy. Also, although no cancer cells have spread to Grace’s cerebrospinal fluid she will need to have drugs injected intrathecally, directly into her spinal column, in order to prevent future spreading to the spinal fluid. Methotrexate will be delivered probably twice within her month of treatment via a Lumbar Puncture, as previously described and pictured in Figure 2. Methotrexate interacts with folic acid in the cancer cells making them folic acid deficient, leading to cell death.[14]

Radiation therapy also is used in treating acute lymphoblastic leukemia that has metastasized, or spread to other locations in the body. Because this is currently not the case for Grace, she will not require radiation treatment at this stage in her condition. Radiation is known to cause secondary tumors, so forgoing this in Grace’s therapy is very beneficial for her long-term recovery. Also, because Grace's is young and her brain is still developing, radiation could cause serious learning disabilities and brain damage that she will have to combat for the rest of her life. If the cancer does spread to her cerebrospinal fluid during treatment, however, she will have to undergo radiation treatment to her brain via external beams.

Targeted therapy plays no role at this stage in Grace's cancer, as the most common form of targeted therapy utilizes TKI, tyrosine-kinase, inhibitors to kill off cells with the Philadelphia chromosome, which Grace is negative for.[15] Stem cell transplants are also only associated with much higher risk cases of leukemia. If a patient is beyond other curative methods they usually are given extremely high doses of chemotherapy along with a stem cell transplant. Allogenic stem cell transplants are the only type used for childhood leukemia. This means that the blood stem cells will come from the bone marrow of another person, not their own.[16]

Aside form Grace’s chemotherapy regimen, it may also be possible for Grace to partake in a clinical trial sponsored by the Children's Oncology Group. The oncologist encourages Grace’s parents to enroll if Grace is selected, as those patients that do participate in clinical trials have shown to have a higher cure rate. This trial is in its third phase and currently recruiting child patients by random selection with standard risk acute lymphoblastic leukemia. Because the trial is in it’s third phase, it has already been tested on small and large groups to ensure it’s safety. The trial will not differ much from her already recommended chemotherapy as it will test different combinations of the same drugs to see which work best together, and primarily what dosages and duration of the drugs result in the least severe symptoms. If Grace's cancer progresses and new mutations are introduced, she could be eligible for a clinical trial that is more specifically targeted at her cancer cells, but currently this is the only trial applicable to her case. [17]

Part III
After reviewing this treatment plan, Grace's parents express concern over the symptoms corresponding to the chemotherapy drugs, and want to better understand how this treatment will be successful. Additionally, Grace has a younger sister, which poses another concern for her parents relating to the disease. They want to understand better how Grace became susceptible to the cancer and why, to judge whether their other daughter has the same risks of developing leukemia. To begin alleviating these concerns, the oncologist offers to explain the potential origins of Grace’s acute lymphoblastic leukemia.

To understand Grace’s leukemia it is first important to know the mechanisms in which cancer operates, specifically two main hallmarks: enabling proliferative cell growth and inhibiting tumor suppressors. To enable proliferative cell growth, proto-oncogenes, which are normal genes that code for growth regulating proteins, have to be mutated to oncogenes. These oncogenes are an enabling trait of cancer as they have obtained the ability to constantly produce their protein product and promote continuous cell growth and growth signaling. Alone, oncogenes will not cause cancer however, because tumor suppressor genes exist, which are in place to inhibit cancer activity. In order for the potential cancer cells to surpass these regulators, both alleles of a tumor suppressor gene usually must be mutated, resulting in the gene’s loss of function. In an individual with cancer, certain tumor suppressors no longer function as checkpoints to prevent the cell from replicating, while mutated oncogenes promote continuous replication. As a result, these cells with numerous mutations will continue to replicate without regulation, and in conjunction with various other mechanisms, a person will develop cancer.[18]

These two concepts apply most directly to Grace’s cancer, as at her stage of leukemia, the disease has not metastasized. From a molecular standpoint, Grace’s lymphoid stem cells are producing a large number of immature B-lymphocytes, a type of white blood cell that would normally go on to produce antibodies. These immature lymphocytes are crowding out the healthy B and T lymphocytes present and natural killer cells, largely impairing her immune system and resulting in her current cancer symptoms.
Figure 3: Signal Pathway of a RAS Protein

To understand the odds of Grace’s sister developing leukemia and also how well Grace’s treatment will work, a key question to ask is how Grace’s cells were able to become cancerous. A likely answer would be that some cells acquired various mutations allowing changes in the functions of some of these proto-oncogenes and tumor suppressor genes, further enabling the cell to replicate uncontrollably.

One common mutation in childhood acute lymphoblastic leukemia is that of the N-RAS proto-oncogene. The N-RAS gene product typically regulates cell growth through signal transduction as shown in Figure 3. This means the protein formed by the N-RAS gene relays messages from outside of the cell to the cell nucleus about whether it should replicate or not. N-RAS is not the only step in this signal cascade, but it does play a very large role due to the many different pathways it comes into contact with. Missense mutations of N-RAS have been most commonly documented in acute leukemia. This means there is a mutation of a single nucleotide in the DNA of the N-RAS gene that makes it code for a different amino acid. This accounts for the noticeable change in protein function, as it begins to constantly promote cell replication even when external signals tell the cell to stop replicating on account of various external and internal factors.[19] [20]

Other likely mutations in Grace’s cells are those of the tumor suppressors RB1 and TP53. Though neither is involved in the initiation of the cancer, when mutated they play large roles in its progression. Both of these genes acquire a mutation of some sort, commonly a point mutation, which is a change in a single nucleotide base. This results in a loss of the gene’s ability to block various tumor- inducing proteins, further enabling the cell to grow uncontrollably.[21]

These mutations only occur in about 15-25% of cases, so these specific genes may not be those mutated in Grace’s cancer cells. That being said, the genes involved will compromise very similar pathways allowing the cancer cells to proliferate in the same way. So whether or not N-RAS or TP53 are involved, understanding these mechanisms is sufficient information in planning a treatment at this time. Grace’s parents question whether a genetic test should be done to understand both what somatic, or acquired, mutations have occurred as well as any germline mutations, those inherited from family. If there were germline mutations present and involved in the development of the cancer, this could lead to a better understanding of the cancer’s hereditary risk. The oncologist reassures them, however, that because there is no family history, and very few cases of acute lymphoblastic leukemia are associated with inherited genetic mutations, her risk is no higher than any other child and this process is unnecessary. Also, this chemotherapy regimen alone should target those mutations at play in Grace’s cancer while in it’s early stages, and if not, they will consider testing later during an intensification phase.[22]

Without knowing the specific mutations implemented, the general mechanisms in which the cancer is developing can still be assumed. This is because regardless of the gene mutated, the mutations will be enabling unregulated cell growth by the two methods previously discussed. This understanding of the molecular basis alone allows for a proper treatment to be selected for. The mixed chemotherapy regimen selected by the oncologist will target Grace’s cancer at its current state while minimizing the toxicity and side effects of using higher doses in conjunction with other forms of therapy, such as radiation. To treat Grace’s cancer, the oncologist prescribed Vincristine and L-asparagine. At this stage in the disease, it is clear that treatment will be implemented to both stop these immature B-lymphocytes with these acquired mutations from replicating further, and also kill them to prevent the cancer from spreading now or in the future. Both Vincristine and L-asparaginase will work in different ways to achieve this goal.

Vincristine, as previously stated, inhibits the formation of microtubules in the mitotic spindle resulting in an arrest of cell division at the metaphase stage. When Vincristine enters Grace’s blood stream it will target all cells, but primarily the rapidly dividing cancer cells, as they are constantly in and out of mitosis. This will prevent the non- resistant cells from dividing further than the metaphase stage and subsequently the cancer from continuing to spread.[23] If cells are found to be resistant, they will be targeted after the induction phase with a new or more intensive treatment. Vincristine will hopefully be able to inhibit the cancer cells from replicating further, as it will shut down all cells attempting to move through the cell cycle.

L-asparaginase catalyzes the conversion of L-asparagine, an amino acid produced in the cells necessary for the function of these lymphoblasts, along with other cells. In normal cells, a lack of L-asparagine can be compensated for by an alternative synthesis using aspartic acid and glutamine. However, cancer cells are not able to synthesize very much L-asparagine and rely on their surrounding environment for the large supply needed to maintain their rapid growth. Without this supply, replication of DNA and RNA is inhibited in the leukemia cells, resulting in apoptosis, or cell death.[24] This inhibition will eventually kill off the cancer cells present in Grace’s bone marrow, while her normal cells will be able to bounce back

This combination of drugs works to stop growth of cancer cells, which have adapted mutations such as the N-RAS oncogene, enabling them to grow uncontrollably. Also, killing these cells off will hopefully be able to prevent those cells from advancing and becoming resistant to therapy. Chemotherapy drugs that operate in this manner are best for patients in Grace’s stage of leukemia as they minimize side effects while also attempting to stop those cancer enabling characteristics in their tracks. There are alternative targeted therapies, more specific to the molecular makeup of leukemia. These would focus on inhibiting cells with specific mutations, such as the Philadelphia chromosome. That being said, no targeted therapies apply to a cancer at such an early stage as Grace’s. There is little known about the pathogenesis of leukemia, so rather than attempt to treat based on specific pathways, it is best to administer a combination of chemotherapy drugs capable of stopping mutated cells from proliferating further and evolving. If Grace’s leukemia were to not respond to her chemotherapy treatment after her induction phase, then she would potentially be considered for one of these more specific treatments and further cytogenetic analysis.

Another reason this mixed chemotherapy should be successful for Grace’s case is that her cells express hyperdiploidy, a chromosome number greater than 46. Studies show hyperdiploidy is highly beneficial in chemotherapy treatment, though reasons are still not fully understood. This advantage could be because by the cancer cells having an unusually high number of chromosomes, they also become very unstable. This chromosomal instability would put more stress on the cell so that once chemotherapy treatment is implemented they would be more prone to apoptosis, another reason the oncologist is hopeful for Grace’s chemotherapy treatment. [25]

After a detailed explanation of Grace’s cancer as well as the role of these drugs at a molecular level, her parents feel much more optimistic about her treatment plan and hopeful in it’s ability to cure their daughter’s cancer in it’s early stages. They are also more at ease knowing that the disease is not likely due to any hereditary factors and their younger daughter does not have an increased risk.

With her parent’s approval, the oncologist starts Grace on her mixed chemotherapy regimen. For the next month she will be in and out of the hospital for injections and checkups. By the end of the first round, if her prognosis holds true, Grace should have little to no minimal residual disease and most of the cancer symptoms should have subsided. It is important to remember the chemotherapy is still highly toxic and at such a young age her likelihood for future complications increases dramatically after taking the drugs. That being said, the odds that Grace will get to live out her childhood and into her adult years, without further complications, are very much in her favor.

Acute Lymphoblastic Leukemia is typically thought to be a devastating illness, however it has a remarkable survival rate among child patients. For a child like Grace, chemotherapy drugs have the potential to rid her of leukemia entirely and ensure far more benefits than consequences.
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