Acute Lymphocytic Leukemia (ALL)

Acute Lymphocytic Leukemia (ALL) is a B or T lymphoblastic neoplasm characterized by abnormal development of aberrant, immature cells and their precursors, which eventually results in the replacement of bone marrow and other lymphoid tissues, resulting in the classic Acute Lymphocytic Leukemia clinical pattern. In the United States, Acute Lymphocytic Leukemia represents about 2 percent of all lymphoid malignancies identified. Males are somewhat more likely than females to have Acute Lymphocytic Leukemia, and Whites are three times more likely than Blacks to develop the disease. Because the tumor has replaced the bone marrow, patients with Acute Lymphocytic Leukemia usually have symptoms like anemia, thrombocytopenia, and neutropenia. Tiredness, frequent or spontaneous bruising/bleeding, and infections are all possible symptoms. Fever, nocturnal sweats, and unintended weight loss are common B-symptoms, but they might be minor. On presentation, liver enlargement, spleen enlargement, and lymphadenopathy can be detected in approximately half of the individuals. Central nervous system involvement is common, and it might be associated with cranial neuropathies or symptoms, mostly meningeal, that are connected to increased intracranial pressure.

What is Acute Lymphocytic Leukemia ALL?

Acute lymphocytic leukemia is one of the different types of acute leukemia. Acute lymphoblastic leukemia is another name for it. If it isn't treated, acute implies that it will typically develop worse soon. The most frequent type of cancer in children is acute lymphocytic leukemia. Adults can be affected as well.

The bone marrow produces an excessive number of lymphocytes, a kind of white blood cell, in Acute lymphocytic leukemia. Normally, these cells aid in the defense against infection in the body. However, they are all aberrant and unable to combat infection effectively. They also crowd out good cells, making infection, anemia, and frequent bleeding more likely. These aberrant cells have the potential to spread throughout the body, including the brain and spinal cord.

Epidemiology

In the United States, acute lymphocytic leukemia is the most frequent type of malignancy and leukemia in children. The average age at the time of diagnosis is 16 years. Acute lymphocytic leukemia is the most common type of leukemia in children, accounting for 74 percent of all cases.

Acute lymphocytic leukemia is less prevalent in adults than acute myeloid leukemia (AML). According to the American Cancer Society, 5700 patients with Acute lymphocytic leukemia (adult and children) will be diagnosed in the United States in 2021, with 1600 people dying. The 5-year survival rate is projected to be 69 percent. The excellent cure rate of Acute lymphocytic leukemia in children accounts for the positive survival rate. With advancing age, the prognosis deteriorates, and the average life expectancy is 55 years.

Italy, the United States, Switzerland, and Costa Rica have the highest numbers of Acute lymphocytic leukemia in the world. B-cell progenitor Acute lymphocytic leukemia has been growing by about 1 percent per year in Europe as a whole.

Acute Lymphocytic Leukemia Etiology

Greaves determined that B-cell progenitor acute lymphocytic leukemia has complex pathogenesis, with a two-step process of gene mutation and infection having a key role, in a study of the genomes, cell biology, immunology, and epidemiology of pediatric leukemia. The first phase takes place in gestation when hidden, pre-leukemic cells are generated via fusion gene production or hyper-diploidy. The second step is the accumulation of secondary genetic changes after birth, which leads to obvious and blatant leukemia transformation. Only 1 percent of children who are born with pre-leukemic cells develop leukemia.

Infection initiates the second stage. Invoking is more frequent in kids who have an improperly controlled immune reaction as a result of not being subjected to viruses during their first few weeks or months of life. Limited exposure to such early viruses, which train the immune response, is more likely to occur in communities that are too concerned with hygiene; this could illustrate why infant acute lymphocytic leukemia is currently only seen in industrialized countries.

In comparison to acute myeloid leukemia, the pathogenesis of acute lymphocytic leukemia in adults is less well understood. The majority of persons with acute lymphocytic leukemia have no known risk factors.

Although most leukemias caused by radiation exposure are acute myeloid leukemia rather than acute lymphocytic leukemia, survivors of the Hiroshima atomic bomb had a higher prevalence of acute lymphocytic leukemia than those who survived the Nagasaki atomic bomb.

Secondary Acute Lymphocytic Leukemia

The occurrence of acute lymphocytic leukemia was above the anticipated in individuals with a previous history of Hodgkin lymphoma, small cell lung carcinoma, or ovarian cancer.

An antecedent hematologic disease (AHD) such as myelodysplastic syndrome that progresses to acute lymphocytic leukemia is seen in a small percentage of patients. However, instead of acute lymphocytic leukemia, most individuals with myelodysplastic syndrome who get acute leukemia have acute myeloid leukemia. Secondary acute lymphocytic leukemia has occurred in some patients taking lenalidomide as a treatment for multiple myeloma. According to research conducted by the California Cancer Registry, 3 percent of patients had a past recognized malignancy, and any previous cancer increased the risk of developing acute lymphocytic leukemia. In comparison to patients with de novo acute lymphocytic leukemia, these patients with secondary acute lymphocytic leukemia had a poor prognosis.

Genetic Predisposition

Other research has linked Single-nucleotide polymorphisms in the following genes to an increased risk of acute lymphocytic leukemia:

Arylamine N-acetyltransferases 1 and 2
MMP-8 promoter genotypes
HLA alleles
ARID5B
CEBPE
CDKN2A
PIP4K2A
LHPP
ELK3

Acute Lymphocytic Leukemia Pathophysiology

Acute lymphocytic leukemia abnormal cells are lymphoid precursor cells (i.e., lymphoblasts) that have been stopped in their maturation. An aberrant expression of genes, frequently as a result of chromosomal translocations or chromosomal number anomalies, causes this stop.

The amount of normal bone marrow components that form other blood cell lines is reduced as these abnormal lymphoblasts grow (red blood cells, platelets, and neutrophils). As a result, anemia, thrombocytopenia, and neutropenia develop, but to a minor extent than in acute myeloid leukemia. Lymphoblasts can also invade organs beyond the bone marrow, such as the liver, spleen, and lymph nodes, causing them to enlarge.

Acute Lymphocytic Leukemia Symptoms

Acute lymphocytic leukemia sufferers have signs and symptoms related to leukemic cells directly infiltrating the bone marrow or other structures, or signs and symptoms related to the diminished generation of normal marrow components.

Fever is one of the most prevalent symptoms of acute lymphocytic leukemia, and people with the disease frequently have a fever while having no other indicators of infection. However, regardless of evidence, all fevers in such patients must be assumed to be caused by infections, because neglecting to treat infections quickly and effectively can be lethal. Infections are still the leading cause of death among people with acute lymphocytic leukemia.

Irrespective of whether the total white blood cell (WBC) count is reduced, normal, or increased, patients with acute lymphocytic leukemia generally have low neutrophil levels. As a consequence, these people are more likely to become infected. The absolute neutrophil count (ANC), which is calculated as the number of mature neutrophils and bands every given volume, is inversely associated with the incidence and severity of infections. When the absolute neutrophil count is less than 500/L, infections are common, and they are most serious when it is less than 100/L.

Anemia tiredness, headache, tachycardia, and breathlessness, which can occur even after light exercise. Other people may experience bleeding as a consequence of thrombocytopenia (low platelet count) caused by marrow replacement. Furthermore, about 10 percent of patients with acute lymphocytic leukemia have disseminated intravascular coagulation (DIC) when they are diagnosed. Bleeding or coagulant problems may occur in these patients. Some people have lymphadenopathy that can be felt. Others, notable individuals with T-cell acute lymphocytic leukemia, have symptoms including breathlessness that are associated with a big mediastinal tumor.

Bone pain is a common symptom of extensive infiltration of the bone marrow by leukemic cells. This ache can be intense, and its location is frequently unexpected.

Although the presence of large numbers of lymphoblasts in the bloodstream can cause symptoms of leukostasis (e.g., respiratory distress, disrupted mental health status), leukostasis is much less prevalent in persons with acute lymphocytic leukemia than in patients suffering from acute myelogenous leukemia, and it only happens in patients with the highest White cell counts. Renal failure can occur in patients with a significant tumor mass.

Acute Lymphocytic Leukemia Diagnosis

The diagnosis of ALL is based on the following:

A complete blood count (CBC) and a peripheral blood smear are two tests that are used to determine the health of a person.
Analysis of the bone marrow
Study in histochemistry, genetic analysis, and immunophenotyping

When blast cells of lymphoid lineage account for 20 percent of bone marrow nucleated cells or 20 percent of non-erythroid cells when the erythroid proportion is greater than 50 percent, it is diagnosed as acute lymphoblastic leukemia. If bone marrow cells are low or absent, a peripheral blood specimen can be used to diagnose the disease using the same parameters.

The first investigations are a CBC and a peripheral smear; pancytopenia and peripheral blasts indicate acute leukemia. Blast cells can account for up to 90 percent of the white blood cell count in a peripheral blood smear. In the differential diagnosis of severe pancytopenia, aplastic anemia, viral diseases such as infectious mononucleosis, vitamin B12 insufficiency, and folate deficiency should be investigated. High blast numbers are never seen in leukemoid reactions to infectious disease (significant granulocytic leukocytosis [i.e., WBC > 50,000/mcL, > 50 109/L] formed by normal bone marrow). Auer rods (straight azurophilic aggregates in the cytoplasm of blast cells) are never found in acute lymphoblastic leukemia.

The evaluation of the bone marrow (aspiration and needle biopsy) is performed on a regular basis. The percentage of blast cells in the bone marrow is usually between 25 and 95 percent.

Immunohistochemistry, genetic, and immunophenotyping tests can help differentiate acute lymphoblastic leukemia blasts from those caused by acute myeloid leukemia or other diseases. The staining for terminal deoxynucleotidyl transferase (TdT), which is high in lymphoid cells, is used in histochemical research. In order to categorize acute leukemias, certain immunophenotypic indicators such as CD3, CD19, CD20, and CD22 must be detected. T (9;22) in adulthood and t (12;21) and severe hyper-diploidy in kids are common chromosomal anomalies in acute lymphoblastic leukemia.

Hyperuricemia, hyperphosphatemia, hyperkalemia, hypocalcemia, and increased lactate dehydrogenase are some of the other test abnormalities that suggest a tumor lysis syndrome. Low blood sugar and increased serum hepatic transaminases or creatinine may also be evident. Elevated white blood cells are common in individuals with Ph+ acute lymphocytic leukemia and those with t(v;11q23) including MLL rearrangements.

In individuals with central nervous system symptoms, Computed tomography of the head is performed. Computed tomography of the chest and abdomen is recommended to look for mediastinal tumors and lymphadenopathy, as well as hepatosplenomegaly. To test basal heart function, echocardiography or multi-gated acquisition scanning is commonly used.

Acute Lymphocytic Leukemia Treatment

Acute lymphoblastic leukemia is effectively treated by doctors who have long knowledge in treating acute leukemia patients. Furthermore, these patients should be treated in an environment that provides adequate supportive care (e.g., high-level blood banking and leukapheresis). Patients hospitalized without adequate blood product support, leukapheresis facilities, or physicians and nurses knowledgeable with the management of leukemia patients should be transferred to a suitable (usually tertiary care) facility.

Induction, consolidation, maintenance, and central nervous system (CNS) prophylaxis are the four traditional components of acute lymphoblastic leukemia treatment.

The following are some examples of commonly utilized treatment modalities:

Hyper-CVAD (hyper-fractionated cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone)
CALGB 8811 regimen
GRAALL-2005 regimen
Linker 4-drug regimen
MRC UKALL XII/ECOG 2993 regimen
ALL-216

Patients with acute lymphoblastic leukemia must be admitted to the hospital for induction chemotherapy and must be readmitted for consolidation chemotherapy or treatment of chemotherapy adverse reactions. The implantation of a central venous catheter, such as a triple lumen or Hickman catheter, may necessitate surgical intervention.

Induction Chemotherapy

Induction therapy typically consists of either a four-drug treatment plan of vincristine, prednisone, anthracycline, and cyclophosphamide or L-asparaginase provided over the duration of 4-6 weeks, and an asparaginase product, or a five-drug treatment plan of vincristine, prednisone, anthracycline, cyclophosphamide, and an asparaginase Complete remissions are achieved in 65-85 percent of patients using this method.

The hyper-CVAD regimen, which is centered on the efficacy of relatively brief, dose-intensive chemotherapy protocols in children, is an alternative. It combines dexamethasone and vincristine with hyper-fractionated cyclophosphamide and heavy doses of cytarabine (Ara-C) and methotrexate.

A tyrosine kinase inhibitor is added to the hyper-CVAD combination in patients with Ph+ leukemia, and rituximab is added to the hyper-CVAD treatment in patients with CD20 positive leukemia. Both of these treatments have contributed to higher disease-free survival rates.

The rate at which a patient's condition goes into complete remission is linked to therapeutic response. Several researchers have discovered that patients whose disease reaches complete remission within 4 weeks of treatment have higher disease-free survival and survival rates than those whose disease reaches remission after 4 weeks.

Consolidation Chemotherapy

Many research back up the use of consolidation chemotherapy in the treatment of acute lymphoblastic leukemia. In adults with acute lymphoblastic leukemia, Fiere et al tried to compare consolidation therapy with daunorubicin and cytosine arabinoside (Ara-C) versus no consolidation therapy, finding that patients receiving consolidation and maintenance therapy had a 38 percent 3-year leukemia-free chance of survival in comparison to 0 percent for all those receiving maintenance therapy alone.

In a trial published by Hoelzer et al, patients who were in remission after induction received dexamethasone, vincristine, and doxorubicin consolidation therapy, followed by cyclophosphamide, Ara-C, and 6-thioguanine starting at week 20. During weeks 10-20 and 28-130, the patients also got 6-mercaptopurine and methotrexate as maintenance therapy. At the time, the 20-month average remission was one of the longest ever reported.

Early escalation with Ara-C, etoposide, thioguanine, daunorubicin, vincristine, and prednisone at five weeks; late escalation with the same treatment at 20 weeks; both; or neither were the options in the UK Acute Lymphoblastic Leukemia XA trial. At five years, the disease-free survival rates were 34 percent, 25 percent, 37 percent, and 28 percent, respectively. These findings show that early escalation is preferable to late intensification.

Consolidation therapy with Ara-C in conjunction with an anthracycline or epipodophyllotoxin is frequently included in standard 4- to 5-drug induction treatments because most investigations have shown that it is beneficial. As consolidation therapy, patients who get hyper-CVAD induction receive alternate regimens of high-dose methotrexate/high-dose Ara-c and hyper-CVAD.

Maintenance Chemotherapy

In adults with acute lymphoblastic leukemia, the efficacy of maintenance chemotherapy has not been tested in a controlled clinical trial. However, when compared to historical controls, several phase II studies without maintenance medication have shown bad outcomes.

Although maintenance seems to be important, it does not seem that utilizing a more intense versus a less intensive routine is advantageous. There was no difference in disease-free survival between the two groups when maintenance therapy was increased from a 12-month course of a four-drug regimen to a 14-month course of a seven-drug regimen.

POMP is commonly used as maintenance therapy for patients who have received hyper-CVAD induction therapy.

As more patients are recommended for transplant when in initial remission, the proportion of patients who complete consolidation and maintenance therapy has decreased. The use of alternative donors has increased the rate of transplants, making it less likely that a patient may be unable to find a match.

CNS Chemoprophylaxis

Individuals with acute lymphoblastic leukemia typically have meningeal leukemia at the time of recurrence, in contrast to patients with acute myeloid leukemia. Only a small percentage of patients develop meningeal symptoms when they are first diagnosed. As a result, intrathecal chemotherapy for central nervous system prophylaxis is critical.

Cortes et al. examined the frequency of CNS leukemia in four clinical studies at MD Anderson Cancer Center and discovered that high-dose systemic chemotherapy lowers CNS recurrence. Early intrathecal chemotherapy, on the other hand, is required to ensure the least risk of CNS recurrence.

Acute Lymphocytic Leukemia Prognosis

Prognostic variables that are favorable include:

Children who are 3-9-year-old and people younger than 30 years
WBC count less than 25,000/mcL (< 25 × 109/L) or less than 50,000/mcL (< 50 × 109/L) in children
Leukemic cell karyotype with high hyper-diploidy, t(1;19), and t(12;21)
No CNS symptoms at diagnosis

Prognostic variables that are unfavorable include:

Leukemic cell karyotype with 23 chromosomes, with less than 46 chromosomes, or with 66 to 68 chromosomes.
Leukemic cell karyotype with t(v;11q23).
Leukemic cell karyotype t(5;14)/IL3-IG.
Leukemic cell karyotype t(8;14) and t(8;22).
Presence of the Philadelphia chromosome t(9;22) BCR-ABL1.
Increased age in adults.
BCR/ABL-like molecular signature

Initial remission is 95 percent likely in children and 70 to 90 percent likely in adults, irrespective of prognostic variables. More than 80 percent of children have had 5 years of disease-free survival and look to be cured. Only around half of adults survive for more than a year. The following factors contribute to inferior patient outcomes in adults relative to kids:

Having a harder time tolerating intense chemotherapy.
Chronic conditions are becoming more common and severe.
A greater danger ALL chemotherapy-resistance.
Poorer adherence to ALL treatment regimens, which entail outpatient chemotherapy and medical visits on a regular basis.
Treatment regimens inspired by children are used less frequently.

Because the higher risk of and harm from therapy is exceeded by the greater danger of therapeutic failure resulting in death, most investigatory methods choose patients with poor prognostic characteristics for more intensive treatment.

Conclusion

Acute lymphocytic leukemia affects both children and adults, however, it is most common between the ages of 2 and 5. Acute lymphocytic leukemia is thought to be caused by a combination of factors, including external and endogenous exposures, genetic predisposition, and randomness. With risk assessment based on biologic aspects of leukemic cells and response to therapy, therapeutic adjustment based on patient therapeutic effects and genetics, and enhanced supportive care, the survival rate of pediatrics has increased to around 90 percent in recent trials. However, novel ways are required to increase survival while minimizing negative consequences. While most children can be treated, newborns and adults with acute lymphocytic leukemia have a terrible prognosis. Recent genome-wide profiling of germline and leukemic cell DNA has discovered new submicroscopic structural genetic changes and sequence genetic abnormalities that make a significant contribution to leukemogenesis, define new acute lymphocytic leukemia subtypes, impact treatment responsiveness, and may provide new prognostic indicators and targeted therapies for personalized medicine.