Acute myeloid leukemia (AML) is the most common acute leukemia among adults in the US accounting for about 1.1% of all new cancers and about 1.8% of all cancer-related deaths. The overall incidence and mortality rate of AML has been stable during the last decade. AML more commonly affects older age individuals with highest incidences observed in individuals aged between 65 to 74 years. The incidence rate of AML is slightly higher in males than in females.
The AML is a disorder in which myeloid blasts (precursor of myeloid cells) start dividing without control. The abnormal blasts get crowded in the red bone marrow and peripheral blood causing a reduction in the number of normal blood cells. The AML cells can spread quickly to different organs like liver, spleen, and lymph nodes. Pathologically AML is defined as the presence of >/=20% myeloid blasts in the bone marrow or peripheral blood. Presence of <20% of myeloid blasts is defined as myelodysplastic syndrome (MDS).
AML Risk Factors
Several epidemiological studies have revealed a number of risk factors that can predispose AML.
Exposure to radiation
History of radiation exposure is one of the most important risk factors for the development of AML.
Individuals who have been treated with certain chemotherapeutic drugs such as alkylating agents, platinum drugs, or topoisomerase II inhibitors are at higher risk of developing AML later, few years after chemotherapy.
Regular exposure to carcinogens like benzene and petroleum products has been indicated to increase the risk of AML.
Certain hematological disorders such as polycythemia vera, essential thrombocythemia, and idiopathic myelofibrosis increase the risk of developing AML. The risk is even higher in case of MDS that can progress to AML.
Some inherited genetic alterations have been reported to be associated with a high incidence rate of AML, for example (e.g.), Fanconi anemia, Ataxia-telangiectasia, Bloom syndrome, Li-Fraumeni syndrome, Schwachman-Diamond syndrome, Kostmann syndrome, and Neurofibromatosis type 1.
Individual with a history of AML in close relatives are considered to be at increased risk of developing AML. The risk is particularly very high in individuals who have an identical twin who got AML at a younger age.
Cigarette smoking exposes the body to various carcinogenic chemicals, which increases the risk of developing AML.
Age and gender
AML is more common among old age individuals and males.
Signs and Sypmtoms of AML
Following are some common signs and symptoms of AML:
- Unexplained weight loss
- Loss of appetite
- Fever and night sweats
- Fatigue and weakness attributable to anemia, other anemia-related symptoms may include shortness of breath and dizziness
- Recurrent infections like pneumonia due to low WBC count (leukopenia)
- Increased bleeding tendency, bruising, frequent or severe nosebleeds, and bleeding gums due to low platelet count (thrombocytopenia)
- Certain type of AML called acute promyelocytic leukemia (APL) is generally associated with bleeding and clotting problems such as deep vein thrombosis and pulmonary embolism
- Enlargement of the spleen and/or liver
- Swelling, pain, and/or bleeding in gums
- Spread of AML cells to skin may cause chloromas (local collections of blasts) and leukemia cutis (raised, nonpruritic rash)
- CNS involvement may cause certain symptoms such as headache, seizures, vomiting, chin numbness, blurred vision, and/or balancing problems
Investigations for AML
If a person is suspected to have AML, some investigations are required to confirm the diagnosis of the disease. Further, these investigations can help in determining an appropriate treatment approach.
Following are some commonly used diagnostic tools for AML:
Blood tests provide very important information that provides direction to the diagnostic workup of AML. Following are the commonly employed blood tests for the diagnosis of the AML:
Complete Blood Cells Count (CBC): This test provides information on the level of RBCs, WBCs, and platelets. Usually, RBCs and platelets are reduced and WBCs may be reduced or increased.
Blood Smear: In this test, a drop of a blood sample is spread on a glass slide and this is observed under a microscope. It helps in detecting any change in the appearance and number of various blood cells.
Apart from above blood tests, blood coagulation tests (disseminated intravascular coagulation panel) and some blood chemistry analyses (the level of creatinine, uric acid, potassium, calcium, phosphorus, and lactate dehydrogenase (LDH) level) may also be employed.
Bone Marrow Aspiration/Biopsy
Aspiration samples contain a small number of cells and biopsy contains a tiny piece of tissue collected from the bone with the help of a biopsy needle. The biopsy sample is then tested in a laboratory and can provide very useful information about the
AML cells such as the type AML, the severity of cancerous changes involved, and the presence of specific defective genes or proteins.
Following are various techniques used for collecting this information:
Immunohistochemistry: In this technique, a very thin portion of biopsy sample is first attached to a microscope glass slide. The sample is then treated with a specific antibody which gets attached to a protein specific to certain types of cancer cells.
Some reagents are then added to the treated sample that causes the bound antibody to change its color. The change in color of the antibody-protein complex can be observed under the microscope, which confirms the type of cancer cells.
Flow cytometry: In this technique, the aspiration sample is first treated with some fluorescent antibodies that get attached to certain specific proteins (antigens) on the surface of cells.
The treated sample is then analyzed using a laser beam and a detector attached to a computer. This test can detect different types of cells along with the quantification of each type of cells.
Cytogenetic Testing: In this technique, chromosomes are evaluated for certain defects which are common in AML. The sample cells are first grown into the culture medium and are observed under a microscope after adding certain reagents that bind only to a specific defective portion of a chromosome.
This test enables detection of chromosomal abnormalities like translocation, amplification, or deletion.
Fluorescent in situ hybridization (FISH): In this technique, a fluorescent RNA probe is used which binds to a specific portion of a chromosome in the sample cells. Then, the sample can be examined under a microscope to determine the presence of certain chromosomal abnormalities like translocation, addition, or deletion.
This technique is very sensitive, fast, and accurate. Thus, this technique is preferably used for detecting chromosomal abnormalities.
Polymerase chain reaction (PCR): This is a very sensitive diagnostic tool which can detect a very small number of leukemia cells with a specific genetic change.
This technique is generally used to diagnose minimum residual disease (MRD) in patients after treatment.
Utility of imaging tests is limited for the diagnosis of AML. However, these tests can be used to detect the involvement of different body parts by leukemia.
Computed tomography (CT) scan
In this technique, detailed cross-sectional images of body organs are generated using x-rays. It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures.
Magnetic resonance imaging (MRI) scan
This technique provides detailed images of internal body structures using radio waves, strong magnetic field, and gadolinium-based contrast material (which is used via intravenous injection to improve the clarity of the MRI images).
It can be utilized for scanning neck, chest, abdomen and pelvis for the diagnosis of any abnormal lymph node or involvement of liver, spleen, or other structures. It is considered very sensitive to detect the involvement of CNS the patients with neurological symptoms.
In this procedure, a sample of cerebrospinal fluid (CSF, a biological fluid that surrounds the brain and spinal cord) is collected with the help of a needle inserted up to the space around the spinal cord through the lower part (lumbar region) of the spine.
The collected sample is then analyzed in a laboratory for the presence of leukemia cells. Generally, >/=5 leukocytes cells/microliters of CSF with the presence of lymphoblasts is considered as the CNS leukemia. This technique can also be used to deliver a treatment to the CSF.
Response Assessment in AML
A complete response means absence of leukemia cells in the blood and <5% blasts in bone marrow. Any sign or symptom of the disease like spleen/liver enlargement should return to normal.
When complete response cannot be achieved after induction treatment, the disease is termed as a refractory disease. Second-line of treatment is usually employed in such cases.
When leukemia cells are detected in blood or any other body part (including CNS) or >5% blasts in bone marrow, after complete remission, it is known as relapsed disease.
Minimal Residual Disease (MRD)
When leukemia cells are undetectable with conventional diagnostic technique after treatment but detectable with a more sensitive technique such as PCR, or flow cytometry, it is known as MRD. Patients with MRD after treatment are more likely to have disease relapse.
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AML Classification and Risk Stratification
The previous classification of AML by French, American, and British (FAB) system (based on AML cells morphology) has been largely replaced with WHO classification system:
AML with certain genetic abnormalities
-AML with a translocation between chromosomes 8 and 21
-AML with a translocation between chromosomes 8 and 21
-AML with a translocation between chromosomes 9 and 11
-APL with a translocation between chromosomes 15 and 17
-AML with a translocation between chromosomes 6 and 9
-AML with a translocation or inversion in chromosome 3
-AML (megakaryoblastic) with a translocation between chromosomes 1 and 22
AML not otherwise specified
-AML with minimal differentiation (M0)
-AML without maturation (M1)
-AML with maturation (M2)
-Acute myelomonocytic leukemia (M4)
-Acute monocytic leukemia (M5)
-Acute erythroid leukemia (M6)
-Acute megakaryoblastic leukemia (M7)
-Acute basophilic leukemia
-Acute panmyelosis with fibrosis
AML with myelodysplasia-related changes
AML related to previous chemotherapy or radiation
Myeloid sarcoma (also known as granulocytic sarcoma or chloroma)
Myeloid proliferations related to Down syndrome
Undifferentiated and biphenotypic acute leukemias (both lymphocytic and myeloid features are present in such cases)
Each of these types consists of different cytogenetic and molecular characteristics. Analysis of cytogenetic and molecular abnormalities play important role in the diagnosis of the disease and to estimate disease prognosis.
Risk Stratification based on Chromosomal Abnormalities
Presence of following abnormalities is generally associated with the favorable outcome: translocation between chromosomes 8 and 21; translocation and between chromosome 15 and 17; and Inversion of chromosome 16.
Similarly, the presence of following cytogenetic abnormalities is generally associated with poor outcome: deletion of part of chromosome 5 or 7; translocation or inversion of chromosome 3; translocation between chromosomes 6 and 9 and between chromosomes 9 and 22; abnormalities of chromosome 11; and complex changes involving several chromosomes.
Risk Stratification based on Genetic Abnormalities
Poor prognosis is indicated by the presence of a mutation in the FLT3 gene, while a mutation in NPM1 gene (without any other change) and CEBPA gene suggest a better outcome.
Other prognostic factors which govern the severity of AML include patient’s age, WBC count, CNS involvement, response to induction therapy, prior hematological disorder. With the progress in understanding about the disease and genetic abnormalities involved, immunophenotypic/cytogenetic characterization has become an important parameter for selecting an appropriate treatment approach.
ACUTE MYELOID LEUKEMIA TREATMENT
The treatment for AML is one of the most complex and intensive cancer therapy programs. The treatment of AML depends on many factors, including but not limited to, the type of disease, patient’s age, WBC count, immunophenotypic/cytogenetic abnormality involved, CNS involvement, and response to induction therapy.
AML treatment generally includes the following phases:
The main aim of induction therapy is to achieve remission, that is, depletion of leukemia cells from the blood and bone marrow. However, this does not mean a cure as some leukemia cells may still exist that are undetectable by conventional diagnostic techniques. Thus, further treatment is usually recommended. Induction treatment usually depends upon the type of AML, age and performance status of the patient.
For a healthy individual, induction treatment usually includes multiagent chemotherapy with or without a targeted agent depending upon the type of AML.
The treatment for AML may also include CNS treatment with intrathecal chemotherapy if the leukemia cells have spread to the CNS. Patients also generally require supportive treatment with blood product transfusion, antibiotics, antifungals, and drugs that raise blood cell count.
The main aim of consolidation treatment is to wipe out any remaining leukemia cells in the body after induction treatment.
Consolidation treatment for otherwise healthy young patient usually includes chemotherapy with or without a targeted drug depending upon the type of AML.
Allogenic or autologous stem cell transplant (SCT) may be considered in high risk and some intermediate risk patients who are good candidates for the same. Older patients with poor performance status usually receive low-intensity therapy based upon the risk-benefit analysis.
The main aim of maintenance treatment is to avoid disease recurrence after induction and consolidation therapy. The maintenance treatment is not recommended for all types of AML but usually given to patients with APML.
Treatment for ACUTE PROMYELOCYTIC LEUKEMIA (APL)
The translocation of the PML gene on chromosome 15 to the RARA gene on chromosome 17 [t(15;17] producing a PML-RARA fusion gene is the characteristic feature of APL. Patient with APL may have fatal coagulopathy and it is recommended to start treatment even before confirmation of the disease with cytogenetic testing.
After consolidation therapy, bone marrow samples from patients are assessed for MRD using PCR technique. Some patients may receive maintenance therapy with ATRA with or without 6-mercaptopurine and methotrexate for around 1 to 2 years. A periodic monitoring of MRD with PCR technique is recommended for up to 2 years.
Treatment for APL is frequently associated with differentiation syndrome (constellation of symptoms and physiologic abnormalities, including fluid retention, dyspnea, episodic hypotension, pulmonary infiltrates, and pulmonary or pericardial effusions) which should be managed with prophylactic corticosteroid treatment.
Coagulopathy, another common complication encountered in patients with APL, should be managed by transfusion support to maintain platelet counts >/=50,000/microliters, by fibrinogen replacement with cryoprecipitate and frozen plasma to maintain a fibrinogen level of 150 mg/dL, and by the maintenance of prothrombin time and partial thromboplastin time close to normal.
Treatment of AML in patients younger than 60 years and good performance status
For patients with age less than 60 years and who are otherwise healthy (without accompanying comorbidities), the preferred induction treatment regimen include cytarabine + anthracycline. Human leukocyte antigen (HLA) typing and allogenic stem cell transplant is recommended to be performed in high risk and some intermediate risk patients who are the good candidate for it.
A bone marrow aspirate or biopsy should be performed 14 to 21 days after the start of induction therapy to assess the response. If patient achieves a CR after induction therapy, consolidation treatment is started. The preferred consolidation treatment regimen mainly includes HiDAC (high dose Ara-C).
Treatment of AML in patients older than 60 years or poor performance status
For patients with age more than 60 years OR who are not overall healthy (have accompanying comorbidities), the preferred induction treatment regimen includes lower-intensity therapy with hypomethylating drugs 5-azacitidine or decitabine, or low-dose cytarabine. For patients who are the candidate for intensive induction therapy, standard-dose cytarabine and anthracycline can be employed.
A bone marrow aspirate or biopsy should be performed 14 to 21 days after the start of induction therapy to assess the response. If patient achieves a CR after induction therapy, consolidation treatment is started. Non-myeloablative or reduced-intensity (RIC) SCT can be a good option for selected patients who are good candidates for it.
Brief Description of Various Treatment options for AML
Chemotherapy means treatment with anti-cancer drugs that kill or decrease the growth of rapidly-growing cancer cells. Chemotherapy may be employed in combination with targeted drugs for the management of AML having certain genetic abnormalities for which targeted drugs are available. It may also be injected directly in the CSF for CNS prophylaxis/treatment. It may be associated with side effects like nausea/vomiting, hair loss, fatigue, cytopenias, etc due to its effect on normal body cells apart from cancerous cells.
Targeted drug delivery refers to the preferential or specific delivery of chemotherapy drug to the cancer cells sparing the normal cells. This helps in increased efficacy with decreased side-effects of the chemotherapy drug.
Gemtuzumab ozogamicin (GO)
It is an antibody-drug conjugate (ADC) that consists of a monoclonal antibody (a man-made immune protein) linked to a chemotherapeutic drug. The drug targets the CD33 protein, a protein commonly found on AML cells of most patients. The antibody helps in the targeted action of the chemotherapy drug on the leukemia cells. It is approved for the treatment of adult patients with newly diagnosed CD33-positive AML or relapsed/refractory CD33-positive AML.
GO has also been approved to be included in the induction phase treatment in patients with with core binding factor (CBF) positive AML that expresses CD33. It can also be employed as a single agent treatment for patients who cannot tolerate standard chemotherapy.
CPX-351 is a liposomal (a tiny fatlike particle) formulation of two chemotherapeutic agents– cytarabine and daunorubicin mixed in a molar ratio of 5:1 approved by the US FDA for the treatment of AML with myelodysplasia-related changes (AML-MRC). It is preferentially taken up by leukemia cells, which leads to increased efficacy and decreased side-effects.
It is a multi-targeted tyrosine kinase inhibitor that blocks Fms-related tyrosine kinase 3 (FLT3) and several other proteins found in AML cells. It is approved in combination with standard chemotherapy for the treatment of patients with newly diagnosed AML with FLT3 mutated gene.
It is another multi-kinase inhibitor with FLT3 inhibitor activity, which has been investigated and has shown a beneficial effect in combination with standard chemotherapy drugs for FLT3 mutated AML patients. Other FLT3 inhibitors, such as Quizartinib, Crenolanib, and Gilteritinib, have also shown a beneficial effect when combined with standard chemotherapeutic agents for the treatment of patients with AML and FLT3 mutation.
It is an IDH2 inhibitor, approved for the treatment of adult patients with relapsed or refractory AML and an IDH2 mutation.
It is an IDH1 inhibitor, approved for the treatment of adult patients with relapsed or refractory AML and an IDH1 mutation.
The NCCN guidelines recommend ivosidenib or enasidenib as the frontline therapy for patients who cannot receive intensive chemotherapy with IDH1 or IDH2 mutated AML, respectively.
All-trans-retinoic acid (ATRA)
It is a form of vitamin A, which brings about conformational changes in PML-RARA. This causes the differentiation in immature myeloid cells by removing the differentiation block. Common side effects include headache, fever, dry skin and mouth, skin rash, swollen feet, sores in the mouth or throat, itching, and irritation in eyes.
Arsenic trioxide (ATO)
It’s exact mechanism of action is unknown. It is postulated to have differentiation and cytotoxic effects that help in reducing the myeloid blasts.
Radiation therapy (or radiotherapy) uses high-energy x-rays or other high-energy radiations which are directed to the affected area to kill cancerous cells. An external beam radiation therapy can sometimes be employed for the treatment of CNS leukemia; with high dose chemotherapy before SCT; to reduce bone pain in bones invaded by leukemia cells; and to shrink a tumor in the trachea causing breathing problem.
Stem Cell Transplant (SCT)
SCT is considered as the standard of care for high risk and some intermediate risk patients who are a good candidate for the same. Following are major types of stem cell transplant techniques used for the treatment of AML:
Autologous SCT: In this technique, the patient’s own stem cells are first collected from the bone marrow tissue or peripheral blood (preferred nowadays). Then, the patient receives high-dose chemotherapy with or without radiation therapy to kill the leukemia The collected stem cells are re-administered to the patient which slowly replenish the blood cells in the patient’s body.
In this technique, healthy stem cells to be administered to the patient after high dose chemotherapy are obtained from another person known as the donor. It is very important that donor is a close blood relative (preferably a sibling) so that donor HLA closely matches with that of the patient.
Non-myeloablative transplant (RIC or mini-transplant): In case of older individuals or individuals who cannot tolerate a standard allogeneic transplant procedure, a non-myeloablative transplant can be employed. In this technique, a relatively lower dose of chemotherapy/radiotherapy is used to partially kill the cells in the bone marrow. Then, the patient is infused with stem cells from a donor and newly generated immune cells identify and kill any remaining leukemia cells due to the graft versus leukemia effect. Chances of fatal complication due to graft-versus-host disease still exist.
It is very important to assess the benefits of each treatment option versus the possible risks and side effects before making a treatment decision. Sometimes patient’s choice and health condition are also important to make a treatment choice.
This may help in improving the overall quality of life by providing relief from the symptoms caused by the AML. These include but are not limited to using drugs to reduce pain and other symptoms such as vomiting, fatigue or external-beam radiation therapy for bleeding or pain, etc.
Following are the goals of treating AML:
- Prolongation of life
- Reduction of symptoms
- Improvement in quality of life