Acute Lymphoblastic Leukemia (ALL)

Acute Lymphoblastic Leukemia (ALL) is a type of cancer in which the bone marrow makes too many lymphocytes (8). ALL can progress quickly and can spread from the bone marrow into the bloodstream, which consequently can spread to other areas such as the lymph nodes, central nervous system, liver, spleen, and testicles in males (4). Symptoms of ALL may include fever, fatigue, loss of appetite, pain in bones or abdomen, easy bruising, and painless lumps in neck, groin, underarm, or stomach (4). Acute lymphoblastic leukemia can develop in both children and adults, depending on the chromosomal abnormality, however it is more common among children and teens (8).

The disease burden of acute lymphoblastic leukemia (ALL) largely affects children as it is the most common cancer among children and the most frequent cause of death in those under 20 years of age (5). ALL tends to develop more frequently in males than females and usually presents itself in children aged 3-5 (5,9). The incidence rate of ALL is 3.3 cases per 100,000 children and about 4,000 people in the United States are diagnosed with ALL every year (8).

Although the exact etiology of acute lymphoblastic leukemia is unknown, there are several risk factors that have been associated with its' development (8). Exposure to benzene and ionizing radiation have been strongly linked with the development of ALL (8). Other environmental factors such as past exposure to chemotherapy, pesticides and maternal alcohol and drug use have also been linked with ALL, but lack evidence of a causal association (1,9). Studies have also shown that those with Downs Syndrome are at a 20-fold increased risk of developing ALL (2).

The standard treatment of ALL includes intensive chemotherapy/radiation and other drug regimens (7). This treatment combination most likely cure the cancer, however, about 10% of patients relapse (4). This is when ALL becomes problematic as relapsed ALL is the leading cause of death from childhood cancer (7). Researchers have been working with immunotherapy options to try and build up the patient's immune system.

One innovative breakthrough that has been showing great potential is CAR T-cell therapy, which was just approved by the Food and Drug Administration (FDA) in 2017 (7). After many clinical trials, Kymriah?®, the CAR T-cell therapy approved for patients with ALL, has shown to work on both children and adults in providing long lasting remission using a targeted, biological approach (7). The success of this new advancement is largely attributed to the deep, biological understanding of how ALL impacts the host and how

Biology of ALL

Acute Lymphoblastic Leukemia originates in the bone marrow, where hematopoietic stem cells (HSCs) are found (2). ALL is aggressive and progresses quickly. Under normal circumstances, HSCs can differentiate into either myeloid or lymphoid cells, also referred to as blasts. However, in acute leukemia, these lymphoid and myeloid cells are unable to mature into other cells (2). The major marker for lymphoblasts is a positive nuclear staining for TdT, a DNA polymerase, in the cell's nucleus (2). ALL can have different subtypes depending on whether or not the lymphoblast becomes a B-cell lymphoblast (B-ALL) or a T-cell lymphoblast (T-ALL).

B-ALL

B-ALL is the most common subtype of ALL, accounting for about 85% of cases (2). B-ALL can be identified by surface markers C10, C19, and C20 (6). B-ALL is also most common in infant and pediatric cases. Looking at cytogenetic abnormalities, if there is a translocation of chromosome 12 and 21, there is a good prognosis and this generally happens in children (6). A translocation of chromosome 9 and 22, otherwise referred to as Ph+ or the Philadelphia chromosome, results in a worse prognosis and generally occurs in adults (6). These translocations result in fusion genes. In 25% of cases, t(12;21) produces the gene ETV6–RUNX1 (2).

T-ALL

T-ALL accounts for about 10%-15% of childhood ALL and can be identified by surface markers CD2-CD8 (2). In terms of cytogenetic abnormalities, the most frequent translocations involve T-cell receptors alpha and delta (TRA and TRD), however there are numerous other translocations and deletions that cause these abnormalities (3). This presents as a thymic mass in the mediastinum and mostly occurs in teenagers. Because this thymic mass is compressing on the thymus, it can obstruct the airway leading to respiratory issues (2).

Biological Impact on Host

As previously stated, both subtypes B and T acute lymphatic leukemia result in immature cells. Because they cannot differentiate, those cells start to build up in the bone marrow, making it difficult for other cells to differentiate due to all the crowding. When those cells cannot differentiate, there is a loss of cells that are normally produced in the bone marrow (2). This results in deficiencies of red blood cells (RBCs), white blood cells (WBCs), and platelets.

If the bone marrow is not able to produce enough red blood cells, the host becomes anemic, leading to fatigue, pale skin, and easy bruising. Deficiencies in white blood cell count can leaves the host prone to infections as WBCs are key components of the immune system. Finally, low platelet counts leave the body vulnerable to bleeding as platelets are necessary to form blood clots (2). Another repercussion of the crowding is that eventually, those blasts will spill into the bloodstream, leading to the enlargement of the liver (hepatomegaly), spleen (splenomegaly), and lymph nodes (2).

Biology of ALL Treatment

Most common treatment for ALL is chemotherapy and radiation therapy, which usually produces good results. However, since it is in the blood, chemotherapy cannot cross the blood-brain barrier or the blood-testicular barrier (6). This is why patients may need prophylactic injections of the chemotherapy into the scrotum and the cerebral spinal fluid (6). Transfusions, a key component of supportive care, is also integral in the treatment of ALL.

Transfusions replace the red blood cells and platelets that the host is deficient in, therefore combating some of the associated symptoms (2). Granulocyte transfusions, which are used to replace the white blood cells, combined with antibiotics are used to help the host fight off infections (2). Finally, physicians strongly enforce hydration to prevent electrolyte imbalances that come from the lysis of those immature cells (6). This treatment regimen proves successful in most patients, but still leaves others prone to relapse.

Due to the increased susceptibility to relapse in some patients, researchers set out to develop a treatment that would provide long lasting remission. Unlike chemotherapy, the goal was to develop a therapy that could help the host strengthen its' own, natural immune system to help fight the cancer. More specifically, looking to enhance the T-cells in the blood.

Proposed Solution in Treatment of ALL

Intensive chemotherapy and radiation have worked with most patients in curing ALL, however once those patients relapsed, there was little to no treatment the physicians could offer them at that point (5). Given the burden of disease, relapse rate, and overall effect on childhood mortality, scientists wanted to develop a therapy to combat those issues. One emerging immunotherapy is chimeric antigen receptor T-cell (CAR-T cell) therapy with the goal of strengthening the patient's immune system (7). Unlike chemotherapy, CAR T-cell therapy uses a targeted approach by only killing the threatening cells and not healthy tissue.

CAR T-cell therapy is a type of adoptive cell therapy in which practitioners extract T cells from the blood and add an artificial receptor (chimeric antigen receptor) to the surface (10). In the lab, these cells are made and millions of them are infused back into the patient intravenously. This allows the T cells to latch onto the specific tumor cells and destroy them (10). To do this, scientists find a marker on that tumor that is unique to it. In cases of ALL, the CARs are grown to recognize the CD19 receptor, a common surface marker for B-ALL (10). Once the CAR T-cell attaches to the CD19 receptor, it releases toxic chemicals that trigger that blast's death. The CAR T-cells then keep attaching to other receptors, multiplying as they go, until they are no longer needed (10).

CAR T-cell therapy has produced positive results in both children and adults. One of the biggest advantages of this new therapy is that it only requires a single infusion along with two weeks of inpatient care (11). Since CAR T-cell therapy is a living drug, the benefits can last for many years in case of relapse. Clinical trials have shown long lasting remission, even in more aggressive forms of B-ALL (11). Although CAR T-cell therapy is only approved for the treatment of B-ALL, researchers are working to develop a similar immunotherapy for T-ALL (11).

Like most cancers, acute lymphoblastic leukemia is difficult to cure due to the pathogenicity and virulence of the disease. As discussed before, ALL is an aggressive cancer, and can spread quickly throughout the body impacting vital organs and systems. Treatment of ALL is also difficult because it leaves the host prone to infections since the blasts decrease the amount of white blood cells in the body (2). Current treatment options may cure the cancer, but with a relapse rate of up to 20%, some patients are left with a devastating prognosis (4). CAR T-cell therapy provides long lasting remission for B-ALL patients meaning there is a potential for long-term disease control. This immunotherapy also not only gives patients a less invasive option with minimal side effects, but gives those with no other treatment options a better prognosis. With the potential of other immunotherapies, the overall burden of ALL cases should improve significantly over the next few years.

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