Acute Myelogenous Leukemia (AML)

Acute myelogenous leukemia (AML), also known as acute myeloid leukemia, is a bone marrow cancer in which hematopoietic progenitors are stopped in their maturation at an early stage. The development of more than 20 percent blasts in the bone marrow distinguishes most acute myelogenous leukemia subtypes from other similar blood diseases.

Acute myelogenous leukemia (AML) is the most frequent kind of acute leukemia in adults, accounting for about 80 percent of cases. The incidence of acute myelogenous leukemia in the United States is from 3 to 5 cases per 100,000 people. In only one year, an estimated 20,800 new cases were diagnosed, with over 10,500 people dying as a result of cancer. Acute myelogenous leukemia prevalence rises with age, from 1.5 cases per 100 000 people in patients under 65 to 12.5 cases per 100 000 people in those above 65. Despite the fact that developments in acute myelogenous leukemia treatment have resulted in significant improvements in survival rates, the prognosis is still very bad in the elderly population.

Patients with Acute myelogenous leukemia may experience health problems as a result of bone marrow suppression, organ invasion with leukemic cells, or both. The duration of the event is varied. Blood testing, bone marrow aspiration and biopsy (the definitive diagnostic tests), and genetic abnormalities analysis are all part of the acute myelogenous leukemia workup.

Only a small percentage of acute myelogenous leukemia patients are cured by current standard treatment protocols. As a result, all patients should be assessed for eligibility to participate in well-designed clinical studies. In the absence of a clinical trial, the patient can be treated with conventional therapy. The treatment of adverse consequences of chemotherapy frequently necessitates hospitalization.

Acute myelogenous leukemia Classification

Acute myelogenous leukemia Classification

Acute myelogenous leukemia is divided into several subtypes and precursor malignancies based on morphology, immunophenotype, cytochemistry, and genetic abnormalities, all of which have significant implications for prognosis and therapeutic interventions. The WHO categorization is divided into seven categories, including:

Acute myelogenous leukemia with recurrent genetic anomalies
Acute myelogenous leukemia with myelodysplasia-related alterations
AML caused by treatment
Acute myelogenous leukemia, not otherwise specified
Myeloid sarcoma
Proliferations of myeloid cells linked to Down syndrome
Dendritic cell neoplasm with blast plasmacytoid

For subtypes that aren't otherwise specified, morphologic criteria from the old French-American-British categorization system are employed.

A variant of acute myelogenous leukemia called therapy-related acute myelogenous leukemia is induced by previous treatment with particular anticancer medicines (e.g., alkylating agents and topoisomerase II inhibitors). The majority of therapy-related acute myelogenous leukemia develops up to 9 years after the start of treatment, with alkylating drugs and hydroxyurea having a longer latency than topoisomerase II inhibitors. Chromosome deletions and unbalanced translocations are caused by alkylating chemicals. Del(17)p mutation is caused by hydroxyurea, which also suppresses TP53 activation. Topoisomerase II inhibitors result in balanced chromosomal translocations.

Epidemiology

According to the American Cancer Society, there will be 20,250 new cases of acute myelogenous leukemia in the United States in 2021 (11,235 males and 9015 women). Acute myelogenous leukemia is more common in developed countries, and it affects white people more than other groups.

Acute myelogenous leukemia is more common as people get older. The average age at the time of diagnosis is around 60 years. Acute myelogenous leukemia, on the other hand, affects people of all ages.

Men are more likely than women to develop acute myelogenous leukemia, especially in elderly people. This is likely due to the fact that men are more prone to develop the myelodysplastic syndrome, and severe myelodysplastic syndrome usually progresses to acute myelogenous leukemia. Some have suggested that occupational exposures may be linked to the increased incidence of acute myelogenous leukemia in men.

Acute Myelogenous Leukemia Pathophysiology

In acute myelogenous leukemia, the exact pathophysiology is a maturational stoppage of bone marrow cells in their initial phases of development. The exact mechanism of this halt is unknown; however, it frequently involves chromosomal translocations and other genetic anomalies that cause gene activation or suppression.

There are two diseases that occur from this developmental halt. First, the generation of normal blood cells drops dramatically, resulting in anemia, thrombocytopenia, and neutropenia in variable degrees. Second, the aberrant myeloblasts' fast growth, along with a loss of their ability to undergo programmed cell death, causes them to accumulate in the bone marrow, blood, and, in certain cases, the spleen and liver.

Acute Myelogenous Leukemia Etiology

Acute Myelogenous Leukemia Etiology

Underlying hematological diseases, familial disorders, environmental triggers, and pharmacological exposures have all been linked to the development of acute myelogenous leukemia. Most patients with de novo acute myelogenous leukemia, on the other hand, have no known risk factors.

Preceding Hematological Diseases

The existence of a preceding hematological illness, the most prevalent of which is a myelodysplastic syndrome, is the most common trigger for acute myelogenous leukemia. myelodysplastic syndrome is a bone marrow disorder with an unknown cause that affects mostly elderly people and causes progressive cytopenia over months or even years. Those with low-risk myelodysplastic syndrome seldom develop acute myelogenous leukemia, whereas patients with high-risk myelodysplastic syndrome do.

Congenital Disorders

Bloom syndrome, Down syndrome, congenital neutropenia, Fanconi anemia, and neurofibromatosis are some of the congenital conditions that predispose people to acute myelogenous leukemia. Acute myelogenous leukemia usually strikes these people when they are children, but it can also strike them in their twenties or thirties. Patients with more minor chromosomal mutations, such as polymorphisms in enzymes that detoxify carcinogens, are also more likely to develop acute myelogenous leukemia.

Familial Syndromes

The familial platelet disease with a tendency for acute myelogenous leukemia, an inherited genetic disorder characterized by mild thrombocytopenia, an impairment in platelet activation, and a propensity to develop acute myelogenous leukemia, is caused by genetic alterations in the gene AML1.In a family with three people affected with acute myelogenous leukemia, a mutation of CEBPA (the gene encoding enhancer-binding protein alpha and granulocytic differentiation factor) was discovered. Leukemia can be a symptom of some hereditary cancer syndromes, such as Li-Fraumeni syndrome. Leukemia, on the other hand, is less prevalent than the solid tumors that characterize these disorders.

Environmental Triggers

A link between radiation exposure and leukemia has been established in many studies. Earlier radiologists were discovered to have a higher risk of acquiring leukemia. The risk of leukemia was higher in patients who received therapeutic irradiation for ankylosing spondylitis. Survivors of the atomic bomb blasts in Japan had a much higher risk of developing leukemia.

Tobacco smokers have a slight but statistically meaningful increased risk of having acute myelogenous leukemia. In various studies, those who smoked had a slightly higher risk of acute myelogenous leukemia than people who did not smoke.

Aplastic anemia and pancytopenia are linked to benzene exposure. Acute myelogenous leukemia is common in these people. The erythroleukemia subtype of acute myelogenous leukemia affects many of these patients.

Exposure to Chemotherapeutic Agents

Patients who have previously been exposed to chemotherapeutic drugs can be split into two groups: those who have been exposed to alkylating compounds and those who have been exposed to topoisomerase-II inhibitors. For alkylating agents/radiation exposure, the latency time between drug exposure and acute leukemia is typically 2-6 years, however for topoisomerase inhibitors, the latency period is only 8-11 months.

Patients who have been exposed to alkylating chemicals, either with or without radiation, frequently go through a myelodysplastic phase before developing acute myelogenous leukemia. A myelodysplastic phase does not occur in patients who have previously been exposed to topoisomerase-II inhibitors.

Acute Myelogenous Leukemia Symptoms

Acute Myelogenous Leukemia Symptoms

The signs and symptoms of acute myeloid leukemia are caused by bone marrow suppression, organ invasion with leukemic cells, or both. The duration of the event is varied. Some individuals, particularly those who are younger, have acute symptoms that last for a few days to a week. Others have a longer time to recover, with tiredness or other symptoms persisting for weeks or months. A preceding hematologic condition, such as myelodysplastic syndrome, may be indicated by a lengthier course.

Symptoms of Bone Marrow Failure

Anemia, neutropenia, and thrombocytopenia are all indications of bone marrow failure. Tiredness is the most prevalent symptom of anemia. Patients frequently report a drop in energy during the previous weeks. Other symptoms of this disease include exertional breathlessness, fainting, and anginal chest discomfort in people with coronary heart disease. In fact, in an older patient, myocardial infarction may be the first indication of acute myeloid leukemia.

Despite having a higher overall white blood cell (WBC) count, patients with acute myelogenous leukemia frequently have lower neutrophil counts. Fever is the most common symptom, which can occur with or without particular evidence of infection. Patients with the lowest absolute neutrophil counts (i.e., less than 500 cells/L, particularly less than 100 cells/L) are at the greatest risk of infection.

Episodes of upper respiratory infections that have not resolved despite empiric treatment with antibiotic therapy are common in patients.

Gum bleeding and numerous petechiae are common symptoms. Thrombocytopenia and coagulopathy are caused by disseminated intravascular coagulation, or both can induce bleeding. The lungs, gastrointestinal tract, and central nervous system are all potential life-threatening hemorrhage locations.

Symptoms of Organ Infiltration with Leukemic Cells

Illness signs could be the result of leukemic cells infiltrating an organ. The spleen, liver, gums, and skin are the most frequent sites of infiltration. Infiltration is particularly prevalent in people with acute myelogenous leukemia subtypes that are monocytic. Fullness in the left upper quadrant and early satiety are common symptoms of splenomegaly. Gum infiltration patients frequently go to the dentist initially. Swollen gums can be caused by neutropenia, and bleeding gums can be caused by thrombocytopenia.

Patients with high WBC counts (more than 100,000 cells/L) may experience signs of leukostasis (i.e., respiratory distress and altered mental status). Leukostasis is a medical emergency that necessitates prompt treatment. Additional pressure in the bone marrow can produce bone pain in patients with a high leukemic cell count.

Acute Myelogenous Leukemia Diagnosis

Acute Myelogenous Leukemia Diagnosis

The neoplasm is diagnosed with the following approach:

Complete blood counts and a peripheral blood smear.
Analysis of the bone marrow.
Studies in histochemistry, cytogenetics, immunophenotyping, and molecular biology.

When myeloid blast cells account for less than 20 percent of marrow nucleated cells or less than 20 percent of nonerythroid cells when the erythroid component is greater than 50 percent, or when any blast proportion is present in the presence of frequent cytogenetic abnormalities such as t(8;21), t(15;17), inv(16), or t(16;16), acute myelogenous leukemia is diagnosed. The same parameters can be used to diagnose the disease utilizing peripheral blood.

Complete Blood Count and Peripheral Blood Smear

Complete Blood Count and Peripheral Blood Smear

The first investigations are complete blood counts 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 (WBC) count in a peripheral smear.

In the differential diagnosis of severe pancytopenia, aplastic anemia, viral diseases such as mononucleosis, vitamin B12 insufficiency, and folic acid deficiency should be investigated. High blast numbers are never seen in leukemoid reactions to infectious diseases (marked granulocytic leukocytosis with WBC higher than 50,000/mcL, > 50 109/L] produced by healthy bone marrow).

Bone Marrow Analysis

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

Cytogenetics and Molecular Studies

acute lymphocytic leukemia blasts can be distinguished from those of acute myelogenous leukemia or other disorders using histochemical tests, cytogenetics, immunophenotyping, and molecular biology investigations. Myeloperoxidase, which is positive in cells of the myeloid lineage, is stained in histochemical investigations. Auer rods (straight azurophilic aggregates in the cytoplasm of blast cells) arise when myeloperoxidase-rich granules crystallize, and they are pathognomonic for acute myelogenous leukemia. In order to categorize acute leukemias, particular immunophenotypic biomarkers (such as CD13, CD33, CD34, and CD117) must be detected.

t(15;17), trisomy 8, t(8;21), inv(16) or t(16;16), and 11q23.3 rearrangement are all common cytogenetic abnormalities in acute myelogenous leukemia.

Cytogenetic abnormalities that are less common include:

t(9;11) (p22.3;q23.3) MLLT3-KMT2A
RBM15-MKL1 t(1;22) (p13.3;q13.1)
t(6;9) (p23;q34.1) DEK-NUP214
inv(3)(q21.3q26.2)

High levels of uric acid, phosphate, potassium, calcium, and lactate dehydrogenase are all possible test results. The results point to a tumor lysis syndrome. Low blood sugar and/or increased serum hepatic transaminases and/or creatinine may also be detected.

In individuals with Neurological symptoms, a CT scan of the head is performed. Prior to administering cardiotoxic anthracyclines, an echocardiography or multi-gated acquisition scan is usually performed to examine baseline heart function.

Acute Myelogenous Leukemia Treatment

Medically Fit Patient

Acute Myelogenous Leukemia Treatment

Induction chemotherapy is used first in medically fit individuals to try to promote complete remission. Consolidation therapy, which may involve allogeneic hematopoietic stem cell transplant, is given to patients who are in complete remission.

5 percent blast cells in the bone marrow, absolute neutrophil count higher than 1000/mcL, platelet count higher than 100,000/mcL, and blood transfusion independence are all considered complete remission.

1. Induction chemotherapy

The basic induction regimen involves a 7-day constant IV administration of cytarabine and a 3-day IV administration of daunorubicin or idarubicin. Myelosuppression, infections, and bleeding are common side effects of therapy. Prior to marrow restoration, there is a considerable period of latency. During this time, it is critical to provide rigorous preventive and supportive care.

Complete remission rates range from 70 to 85 percent for favorable genetics, 60 to 75 percent for moderate genetics, and 25 to 40 percent for poor genetics; complete remission rates are also influenced by patient-specific and other disease risk factors. However, most patients who attain complete remission with an induction regimen eventually relapse.

2. Re-induction chemotherapy

Although there is no increased evidence that re-induction improves results, it is routinely suggested for patients with persistent leukemia on day 14. Residual leukemia is defined as a condition in which bone marrow blasts are greater than 10 percent and bone marrow cellularity is greater than 20 percent. Various doses of cytarabine are used in the various re-induction protocols. Anthracyclines, with or without a third agent, are used in some cases.

A variety of medications can be used in conjunction with or instead of standard induction chemotherapy. Midostaurin, a kinase inhibitor, seems to improve survival in some patients (e.g., adults under 60 with recently diagnosed FLT3 mutant acute myelogenous leukemia). In individuals with recently diagnosed CD33-positive acute myelogenous leukemia, gemtuzumab ozogamicin (an anti-CD33 drug combination) can be coupled with chemotherapy. Induction and consolidation with gemtuzumab ozogamicin can also be done as a monotherapy.

3. Consolidation chemotherapy

In many regimens, remission is followed by a consolidation phase. This can be accomplished with the same or different medications that were used during induction. High-dose cytarabine regimens, especially when used for consolidation in individuals under 65 years old, may prolong remission duration. Consolidation with high-dose cytarabine is recommended routine after induction therapy for patients with good cytogenetic in initial full remission.

Adults with recently diagnosed therapy-related acute myelogenous leukemia or acute myelogenous leukemia with myelodysplasia-related alterations can be treated with a liposomal compound of daunorubicin and cytarabine. In patients 65 to 70 years old with recently diagnosed therapy-related acute myelogenous leukemia, this combination exceeded the standard-of-care cytarabine plus daunorubicin regimen in terms of overall survival.

4. Stem cells transplantation

Patients with moderate or adverse-risk cytogenetics can benefit from allogeneic stem cell transplantation during the first full remission. Preparation for a stem cell transplant usually takes 5 to 10 weeks. While preparing for definitive stem cell transplantation, regular high-dose cytarabine consolidation chemotherapy is recommended. Patients with low overall performance levels and moderate to severe compromise of lung, liver, kidney, or heart function may be unsuitable for allogeneic stem cell transplantation.

Medically Unfit Patient

Medically Unfit Patient

Because the average age of acute myelogenous leukemia detection is 68, the majority of recently diagnosed individuals are older. Chronic conditions are more common in older patients, limiting their treatment options. Patients over the age of 65 are also more likely to have a higher cytogenetic abnormality, secondary acute myelogenous leukemia caused by myelodysplastic syndrome, or multidrug-resistant acute myelogenous leukemia.

Although older individuals are often refused intense chemotherapy due to their age, it does improve the number of full remission and survival rates in patients under the age of 75, especially those with advantageous karyotypes. Complete remission also improves the quality of life by lowering the number of hospitalizations, infections, and blood transfusions needed.

Decitabine and azacytidine, DNA methyltransferase inhibitors, are pyrimidine nucleoside equivalents that alter DNA by lowering methylation of tumor suppressor genes' promoter regions. They have enhanced clinical outcomes in patients with de novo acute myelogenous leukemia, therapy-related acute myelogenous leukemia, and acute myelogenous leukemia with TP53 mutations. Many elderly patients, especially those with impaired functional/performance status, organ damage, and tumor genetics (e.g., karyotype, molecular abnormalities) that indicate poor response to intense chemotherapy, can be treated with one of these medications alone as first-line therapy.

Venetoclax is an inhibitor of the anti-apoptotic protein BCL-2 that is used in combination with azacytidine, decitabine, or low-dose cytarabine for the treatment of newly diagnosed acute myelogenous leukemia in persons over the age of 75 who do not require intensive induction chemotherapy due to comorbidities. More research is needed to corroborate these response rates, as well as the indication's sustained support. Glasdegib is a hedgehog pathway inhibitor that is used in combination with low-dose cytarabine to treat newly diagnosed acute myelogenous leukemia in individuals under the age of 75 or who have comorbidities that prevent them from receiving aggressive induction chemotherapy.

Following induction therapy, elderly patients may have allogeneic hematopoietic stem cell transplantation if overall performance status allows it. In older individuals, allogeneic hematopoietic stem cell transplantation improves survival. Reduced-intensity regimens can be utilized if patients are not eligible for full strength regimens. Patients who do not have a transplant are frequently treated with consolidation chemotherapy.

Acute Myelogenous Leukemia Prognosis

Acute Myelogenous Leukemia Prognosis

Physicians can determine whether a conventional therapy or a more intensive therapy would be beneficial in sustaining complete remission and overall survival rates by analyzing prognostic variables. Chromosomal abnormalities (advantageous abnormalities include t(8;21), t(15;17), and chromosome 16 inversion) and gene abnormalities (NPM1 gene has a favorable prognosis, and FLT3 gene has unfavorable prognosis) are prognostic factors. Older age, white blood cell counts higher than 100,000 at the initial diagnosis, and the development of leukemic cells in the central nervous system have all been linked to poorer outcomes.

PCR and flow cytometry are two new approaches that can detect the presence of minimal residual illness in CR patients. In individuals with t(8;21) acute myelogenous leukemia, persistently high levels of RUNX1-RUNX1T1 after induction treatment are linked to a higher risk of relapse.

Conclusion

Acute myelogenous leukemia is a disease with a complicated genetic background. With a better understanding of biology and the possibility for new pharmacological targets, the area is quickly increasing. Despite the best efforts, it has become clear that single drug alternatives may have a lower chance of success when compared to many drug targets. After hematopoietic cell transplantation, the relapsed disease is still the leading cause of death. Immunotherapy is another promising new therapeutic method that may provide relapsed patients with long-term cures. We remain optimistic that pharmaceutical choices will improve in the future, with less toxicity and greater efficacy.