Acute Myeloblastic Leukemia

Introduction

Definition of acute myeloblastic leukemia 

Leukaemia is a type of cancer of the blood. There are different forms of leukaemia depending on the type of blood cell affected. “Acute” describes a rapid progression, and “myeloblastic” denotes the origin from myeloid cells, which are immature cells that normally become mature red blood cells, white blood cells, or platelets. In acute myeloid leukaemia, the bone marrow produces too many early (immature) blood cells which do not go on to become mature blood cells. Platelets play a critical role in stopping bleeding and red blood cells are important in delivering oxygen to all cells in the body. Excess production of immature myleloid blood cells in the bone marrow ultimately prevents the normal production of red blood cells, resulting in anaemia, and decreased production of platelets or thrombocytompenia. Patients with AML seek medical care due to lack of energy and fatigue from anaemia or bleeding and bruising, from insufficient platelets. Without enough normally functioning white blood cells, the body’s immune system also becomes weak and susceptible to infection. Other symptoms include, fever, shortness of breath and bone pain. At diagnosis, most patients - though not all - have a white blood cell count (the number of white blood cells circulating in the blood) that is above normal.

 

GUIDE FOR PATIENTS BASED ON ESMO CLINICAL PRACTICE GUIDELINES
This guide for patients has been prepared by the Anticancer Fund as a service to patients, to help patients and their relatives better understand the nature of Acute Myeloblastic Leukaemia (AML) and appreciate the best treatment choices available according to the subtype of AML. We recommend patients to ask their doctors what tests or types of treatments are needed for their type and stage of disease. The medical information described in this document is based on the clinical practice guidelines of the European Society for Medical Oncology (ESMO) for the management of Acute Myeloblastic Leukaemia in adults. This guide for patients has been produced in collaboration with ESMO and is disseminated with the permission of ESMO. It has been written by a medical doctor and reviewed by two oncologists from ESMO including the lead author of the clinical practice guidelines for professionals. It has also been reviewed by patients’ representatives from ESMO’s Cancer Patient Working Group.

Frequency

Is Acute Myeloblastic Leukemia frequent? 

Compared to breast cancer in women or prostate cancer in men, acute myeloid leukaemia is not common. In the European Union, 5 to 8 cases will be diagnosed among 100,000 people every year. AML is more common in older people, with an almost 10-fold increase in the number of cases among elderly patients.

Causes

What causes Acute Myeloblastic Leukemia?

The cause of acute myeloblastic leukemia (AML) is not understood. A small number of predisposing risk factors have been identified due to catastrophic events, including the atomic bombing of Hiroshima and the nuclear reactor accident in Chernobyl. A risk factor increases the chance of cancer occurring, but it in itself does not cause cancer, and if you have a risk factor, it does not necessarily mean you will develop cancer. A risk factor is not a cause in itself.

Some people with these risks factors will never develop AML and some people without any of these risk factors will still develop AML.

Potential exposure-related risk factors for AML include exposure to radiation, chemicals, and prior chemotherapy.

  • Exposure to radiation: Ionizing radiation directly damages the cell’s DNA creating mutations which either prevent a cell from maturing or cause a cell to proliferate beyond normal. Atomic bomb survivors and radiology technicians prior to 1950 (when protective shielding was first introduced) are at increased risk of developing AML.
  • Exposure to chemicals: Chemicals are associated with increased risk when the exposure is significant in either duration of exposure (such as tobacco smoke) or severity of exposure (benzene and petrochemical exposure involving direct chemical contact).
  • Chemotherapy: previous treatment with high doses of certain anticancer drugs increases the risk of developing AML.

Genetic abnormalities, mutations in the DNA of the cancer cell, commonly occur in AML, however, these mutations are usually not found in other cells of the body. This suggests that the cause of AML is only rarely inherited from one generation to the next. Potential hereditary (passed down genetically from parent to child) risk factors for AML include:

  • Trisomy: This is a genetic abnormality when you have an extra third copy of a chromosome, i.e. one in addition to the those that you you inherited from your mother and father. Normal inheritance patterns result in two copies of each gene. However, as a result of early developmental accidents, a third copy can be inherited. In some cases, a third copy of an entire chromosome (a collection of genes) is inherited, known as a trisomy. Two common trisomies associated with AML are:
    • Trisomy 8: Inheriting a third copy of chromosome 8 results in many skeletal abnormalities as well as increased risk of AML.
    • Trisomy 21: Trisomy 21, also known as Down’s syndrome, increases the risk of leukaemia 10 to 18-fold.
  • Hereditary syndromes: A few rare inherited cancer predisposition syndromes, which are due to known or unknown genetic causes, are associated with increased risk of AML. Such heritable cancer predisposition syndromes include Fanconi’s anemia and Li Fraumeni syndrome.

Prior blood diseases can change or evolve into leukaemia over time. For some blood diseases, the evolution into AML can be prevented by treatment. Myelodysplasia (white blood cells that are abnormal in their shape and size) and myeloproliferative diseases (white blood cells that are overproduced) are the most common blood diseases with an increased risk of developing into AML.
 

Diagnosis

How is Acute Myeloblastic Leukemia diagnosed?

Acute myeloid leukaemia can be suspected in patients due to symptoms or laboratory abnormalities in patients with and without symptoms (asymptomatic). Symptoms may include:

  1. Fatigue. Fatigue is a common symptom due to anaemia (a decreased red blood cell count, often measured as haematocrit or low haemoglobin level). Patients who are physically active may not notice the effects of being anaemic until it is severe.
  2. Infections. Due to replacement of an important part of the normal immune system by cancer, patients can experience recurrent infections, or infections which are unusually difficult to treat.
  3. Bleeding. A low platelet count resulting from replacement of the bone marrow with leukaemia results in easy bruising, bleeding from the nose or gums, petechiae (red spots seen on the skin commonly over the shins and ankles), and purpura (groups of petechiae resulting in larger red skin spots).

Patients who have the above symptoms will have a complete blood count done to check the three types of cells made in the bone marrow: 1) white blood cells, 2) red blood cells, and 3) platelets. Occasionally a patient may have a complete blood count done for another reason, which will be the first indication of a possible leukaemia based on laboratory findings alone. In addition to identifying a low red cell count, or platelet count, the complete blood count may detect, as part of the white blood cell count, leukaemia cells circulating in the blood. Immature white blood cells which are proliferating at an abnormal rate are larger than the more mature normal white blood cells found in circulation.

If a diagnosis of AML is suspected based on symptoms and the white blood cell count, a bone marrow biopsy is performed. In rare cases when the leukaemia cells are found on the complete blood count and the type of AML (see below under treatment of AML) can be determined, treatment may begin prior to a bone marrow biopsy.

A bone marrow biopsy is a minimally uncomfortable procedure lasting about fifteen minutes. Local anaesthesia is used for the procedure and sharp pain is usually not experienced. The procedure allows the pathologist (a doctor trained in diagnosing the disease based on the appearance of cells or tissues in the microscope) to diagnose AML. The pathologist can also determine what type of AML a patient has and further identify the genetic abnormalities of the leukaemia by looking closely at the chromosomes. PCR (polymerase chain reaction, a scientific technique in molecular biology to amplify a single or a few copies of a piece of DNA) and FISH (fluorescent in-situ hybridisation, is a cytogenetic technique that is used to detect and localize the presence or absence of specific DNA sequences on chromosomes) tests are recommended to identify these abnormalities in the laboratory. Prognosis, or the likely outcome, and treatment is based, in part, on the specific mutations identified when examining the chromosomes within the cancer cells. The chromosomes of the leukaemia cells are known as the leukaemia’s karyotype.
 

Treatment

What is important to know to get the optimal treatment?

Doctors will need to consider many aspects of both the patient and the cancer in order to decide in the best treatment.


Relevant information about the patient

  • Personal medical history
  • History of cancer in relatives
  • Results from the clinical examination by the doctor
  • General well-being
  • Typification for bone marrow transplant: many patients with AML may require a bone marrow transplant after their initial treatment. This therapy involves using the bone marrow cells of someone else to replace a patient’s own bone marrow. To prevent the donor’s immune system from damaging the patient’s body (a condition known as graft-versus-host disease), HLA (Human Leukocyte Antigen, a unique set of proteins on each cell) typing must be performed to determine if a donor and a patient have similar HLA types and are a ‘match.’ Since the process of finding a bone marrow donor that matches the patient may take a few months, it is helpful to know the patient’s type when he or she is first diagnosed. HLA typing of the available first-degree family members (parents, siblings and children) who are possible donors should also be performed. If siblings or children are not a match, unrelated donors will be screened. This is one reason that volunteering to be a bone marrow donor is very important. 
  • In addition to clinical examination, other exams may be performed to assess the risks of complications due to the treatment. To assess the cardiac function, an echocardiogram is recommended. To ensure that no infection is currently active in the body, a CT-scan of the chest and abdomen and radiologic examination of teeth and jaw are also recommended. Blood coagulation tests must be performed for patients with acute promyelocytic leukaemia (APL) since coagulation disorders are very frequent in this type of AML. Such tests must be performed before insertion of central intravenous lines.
  • If severe headaches, problems with vision, sensation, or muscle function are present, an assessment of the cerebrospinal fluid, the fluid around the brain and spinal cord may be necessary. This is performed by perofrming a lumbar puncture and sending the fluid to the pathologist to be looked at under the microscope. Imaging examinations including a CT scan or MRI of the head are also often done at the same time as the lumbar puncture. In rare cases the lumbar puncture will not identify any cancer cells and the CT or MRI will show an area of leukaemia inside the brain which will require additional treatment which is specific to this site of tumor.
     

Relevant information about the cancer

  • Classification

Doctors use a classification system to help determine prognosis and treatment. The differentiation of acute promyelocytic leukaemia (APL) from other types of AML is of critical importance to therapy. A specific genetic mutation, resulting from abnormal translocation, or an abnormal rearrangment of genetic material from one chromosome to another (chromosomes 15 and 17) results in this unique form of leukaemia, known as APL. The movement of two chromosomes next to each other is known as translocation.

The movement of the two chromosomes into this new position results in two genes being placed next to each other that are normally separated. The new mutant gene is the cause of APL. The diagnosis of APL is associated with a favourable prognosis and specific treatment regimen including a vitamin therapy, which causes the leukaemia cells to mature.

  • Prognosis and risk classification

Unlike other cancers, which develop at a single site (such as breast cancer within the breast, or prostate cancer within the prostate) and then spread or metastasise, cancer in patients with leukaemia is considered to be present throughout the body at diagnosis due to its normal circulation in the bloodstream. For this reason the prognosis is not determined by the extent of spread of the disease. The prognosis of a patient is best predicted by characteristics of the patient (including and most importantly age) and characteristics of the leukaemia cells. The specific mutations identified within the chromosomes of the leukaemia will classify a patient’s prognosis as good or favourable, normal or intermediate, or poor or unfavourable risk. New mutations are being identified by doctors and their prognosis is being classified into one of these three levels of risk. APL, for example, as discussed above is the result of a translocation of chromosomes 15 and 17, which is a favourable risk mutation, meaning it responds well to treatment. Other favourable mutations include translocation of chromosomes 8 and 21, and inversion of chromosome 16. The presence of multiple, typically greater than three, chromosome abnormalities is associated with poor or unfavourable risk. If no mutations are observed, the degree of risk is considered intermediate.

What are the treatment options? 

The treatment should take place only in centres used to treat AML and offering an adequate multidisciplinary infrastructure. Whenever possible, the treatment should be offered in the form of clinical trials.

Treatment of AML is tailored to the individual based on diagnosis of AML or APL, risk classification based on genetic mutations, and patient characteristics including age and other conditions that the patient may have, such as diabetes, coronary heart disease or chronic obstructive pulmonary disease. Unlike solid tumors, surgical resection and radiation therapy do not typically serve a major role in the treatment of AML.

Immediate (emergency) therapy is needed for patients who present with either extremely high white blood cell counts or with APL.

  • Leukostasis: Normal blood flow to vital organs can be disrupted when the white blood count is extremely high due to circulating leukemia cells. Particularly important is proper blood flow to the lungs, brain, and kidneys. Immediate treatment to reduce the white blood cell count may be necessary. This includes use of a machine, which removes the white blood cells from the blood and returns the red blood cells and platelets to the patient. This is called leukapheresis and is only necessary in emergency situation.
  • APL: Patients who present APL are at increased risk of bleeding. Unlike AML, the bleeding risk is a result of not only low platelets, but also a loss of the proteins that are necessary for the blood to clot appropriately. This condition can be prevented by immediate initiation of treatment with all-trans retinoic acid (a vitamin A derivative) that causes the immature leukaemia cells to mature. The missing proteins can also be replaced by blood transfusions in emergency cases.

Chemotherapy is effective in treating leukaemia since the leukaemia cells are dividing more rapidly than other cells in the body. Side effects from chemotherapy are also mostly limited to dividing cells such as hair, the gastrointestinal tract, the bone marrow (including normal cells in the bone marrow), skin and nails. Chemotherapy for AML is generally grouped into two categories based on level of intensity: intensive chemotherapy and non-intensive chemotherapy.

  • Intensive Chemotherapy
    • Induction chemotherapy requires patients be admitted to the hospital for treatment. The goal of intensive chemotherapy is complete removal of all leukaemia cells within the bone marrow. This allows doctors to provide blood transfusions as necessary and continuous observation for side effects of the intensive chemotherapy. The duration of the initial hospitalisation may be about 4 weeks. Two chemotherapy agents are used most commonly: cytarabine and an anthracycline (known as idarubicin or daunorubicin). The duration of the treatment is approximately 1 week of intravenous infusions. In this process, the normal bone marrow cells are temporarily removed and patients are at risk of infection and may require transfusions of red blood cells and platelets since the body temporarily stops producing its own. 
      One to two weeks after the completion of chemotherapy a bone marrow biopsy is repeated to determine if the response to treatment was appropriate. If no evidence of leukaemia is seen on the bone marrow biopsy, then patients proceed to consolidation chemotherapy. Otherwise a repeat of the induction chemotherapy may be necessary.
      Once the patient’s own normal white blood cells return to normal values, patients are able to safely leave the hospital. Patients may need to see their doctor frequently, however, since additional transfusions of red blood cells and platelets are often still needed for up to 8 weeks after induction chemotherapy.
      If there is still more than 5% immature cells in the bone marrow as seen on the bone marrow biopsy after 1 or 2 induction chemotherapies, the patient is considered as refractory, i.e. not responsive, to treatment. In this case, it is believed that only a bone marrow transplant offers a chance of cure.
    • Consolidation chemotherapy begins once the blood counts recover from induction chemotherapy. The goal of consolidation chemotherapy is to provide a therapy which decreases the chance that the disease will come back in the future. Some patients may be admitted to the hospital for consolidation chemotherapy, which is usually also done with cytarabine (one of the two chemotherapy agents used during the initial induction). The treatment is done over a period of approximately 5 days and repeated monthly for three to four months. The effect of the chemotherapy is not as severe as with the induction chemotherapy and patients do not need to stay in the hospital after the chemotherapy is given. During this time, however, risk of infection is still very high and patients must return to the hospital if a fever develops when the body’s own immune system is weak from the recent chemotherapy.
    • Maintenance/Post-remission therapy is established for APL, but is not well-established for the other types of AML. This therapy is unique for each individual based on their prognosis (described above).
      • APL requires maintenance therapy for approximately one to two years. The therapy combines all-trans retinoic acid (the vitamin A derivative) with two chemotherapies (6-mercaptopurine and methotrexate). 
      • AML (non-APL)
        • Good risk or favourable risk: following consolidation chemotherapy no additional treatment is recommended since the risk of relapse is considered to be less than 35%. A bone marrow stem cell transplant is not justified in first remission because the risk of toxicity and severe complications exceeds the benefit.
        • Poor risk or unfavourable risk: additional therapy including a bone marrow stem cell transplant is recommended. This is the process of transferring someone else’s bone marrow stem cells into the patient. The patient’s white blood cells, red blood cells, and platelets are replaced by the donor’s cells. As the donor’s cells are new to the patient’s body , they can recognise the patient’s cells as foreign, resulting in damage to the patient’s own cells (known as graft-versus-host disease). During the same process the donor’s cells also recognise the patient’s leukaemia as foreign and will destroy it, which is the main beneficial effect of a bone marrow transplant (known as graft-versus-leukaemia effect). Bone marrow stem cell transplants provide an opportunity to eradicate the tumor completely and cure the patient. 
        • Intermediate risk or normal risk: a standard therapy for this level of risk has not been established and patients should seek multiple doctors’ opinions as the treatment should be tailored to the individual. Some studies suggest that a bone marrow transplant should be considered for healthy patients with intermediate-risk disease. 
           
  • Non-intensive chemotherapy
    • Older patients (over 60 years of age) and patients with other medical problems who are not healthy enough to receive intensive chemotherapy can avail of multiple treatment options. These are less intensive and some which not require admission to the hospital. None of these approaches have been established as standard of care and clinical trials should be considered for all patients pursuing non-intensive chemotherapy. Treatment options include:
      • Clinical trial
      • Low-dose chemotherapy (such as cytarabine)
      • Hypomethylating agents (a drug that inhibits the methylation of DNA such as azacytidine), which effect the genetics of the leukaemia attempting to turn on and off genes which cause the cells to proliferate
      • Therapies which target the immune system (such as lenalidomide which is in clinical trials for AML), which modulate the body’s normal immune system to fight the leukaemia and at the same time directly affect the leukaemia cells to cause them to stop dividing and to mature
      • Supportive care, including growth factors to help improve the red blood cell count normal as well as blood transfusions with red blood cells and platelets. Depending on how aggressive the leukaemia may be, life expectancy is very limited without treatment (in some cases only a few weeks or months).
Managing symptoms of the disease and of the treatment

Leukaemia and its treatment can cause severe side effects including diarrhea; nausea; vomiting; hair loss; lack of energy, appetite, and sexual interest; and severe infections. Effective therapies for these side effects exist and patients can expect that some of these problems can be treated.
 

What happens after the treatment? 

It is not unusual to continue to experience treatment-related symptoms once the treatment is over.

  • It is not rare that anxiety, sleeping problems or depression are experienced in the post-treatment phase.  Patients with these symptoms may need psychological support.
  • Memory deficiencies and difficulty in concentrating are not uncommon side effects of chemotherapy and are generally reversible within a few months..

Follow-up with doctors

After the treatment has been completed, doctors will propose a follow-up program, aiming to:

  • detect possible relapse, or return of leukemia as soon as possible
  • evaluate adverse effects of the treatment and treat them
  • provide psychological support and information to enhance returning to normal life

Follow-up visits with the doctor should include

  • History-taking (a review of the patient's medical history) eliciting of symptoms and physical examination
  • A repeat bone marrow biopsy
  • A routine evaluation of the complete blood count every three months.

Return to normal life

It can be hard to live with the idea that cancer can come back. Based on what is known today, no specific way of decreasing the risk of recurrence after completion of the treatment can be recommended. As a consequence of the cancer itself and of the treatment, return to normal life may not be easy for some people. Questions related to body-image, sexuality, fatigue, work, emotions or lifestyle may be a concern for you. Discussing these questions with relatives, friends, other patients or doctors may be helpful. Support from patients organisations providing advice on managing the effects of treatments, as well as psycho-oncologist services, or telephone information services and helplines are available in many countries.

What if the leukaemia comes back?

If the cancer comes back, it is called a relapse or recurrence. The treatment depends on the age of the patient, prior treatment, and possibility of a bone marrow transplant.

Patients who are able to tolerate intensive chemotherapy similar to intensive induction chemotherapy will repeat a similar course of treatment. The chances of success of a new induction therapy are better when the relapse occurs a long time after the first induction therapy. Another possibility for patients with APL is to be treated with arsenic trioxide, which can induce remission.

Following induction for relapsed leukemia, if a sibling or unrelated bone marrow donor can be identified, a bone marrow transplant is recommended. If the leukaemia relapses it is believed that only a bone marrow transplant offers a chance of cure. Patients who relapse following a bone marrow transplant are usually not considered for a second transplant. A clinical trial is the preferred option for patients who relapse following a bone marrow transplant.

Should I consider clinical trials?

Despite the best current therapies, the prognosis for patients with leukemia is poor. The majority of patients will have their disease return after their initial treatment. For this reason, doctors and scientists are researching new therapies. Promising therapies must first be tested among small groups of patients in clinical trials before they are accepted and given to all patients. Clinical trials provide an opportunity to try a new therapy before it would otherwise be available. New therapies also have risks as many of the side effects are unknown until tested. Because of these positive and negative aspects of clinical trials, it is very important that you speak with your doctor about clinical trials, including if and when a clinical trial might be appropriate for you.
  

Synonyms

Acute myeloblastic leukemia

AML

aml leukemia

Acute myeloid leukemia

Acute myelogenous leukemia

Acute myelocytic leukemia

Acute nonlymphocytic leukemia

ANLL

Acute myeloblastic leukaemia

Acute myeloid leukaemia

Acute myelogenous leukaemia

Acute myelocitic leukaemia

Acute nonlymphocytic leukaemia

Acute leukemia

Blood cancer

Bloodcancer

Therapies by type

The following list of treatments is based on what we have found in scientific studies about cancer. More information about the listed therapies can be found under the tab THERAPIES. For registered drugs, radiotherapy and surgical interventions, approval by the authorities is given.

Registered drugs

Anti-cancer drugs with market authorization in the USA or in countries of the European Union. More

Cell-based therapies

Administration to patients of their own or someone else’s manipulated human cells. More

Diets

Controlled consumption of carefully selected foods and beverages with the intent to influence disease outcome.

Clinical trials

A clinical trial is a research study conducted with patients to evaluate whether a new treatment is safe (safety) and whether it works (efficacy). Clinical trials are performed to test the efficacy of drugs but also non-drug treatments such as radiotherapy or surgery and combinations of different treatments. Clinical trials take place in all kinds of hospitals and clinics, but mostly in academic hospitals. They are organized by researchers and doctors.

The Anticancer Fund provides a tool to search for phase III clinical trials by type of cancer and by country. For Belgium, the Netherlands, Switzerland, Luxembourg, France and the UK, the Anticancer Fund provides contacts to get more information about the phase III clinical trials currently ongoing. Discuss the possibilities of participating in one of these clinical trials with your doctor.

The list of the phase III clinical trials for acute myeloblastic leukemia is available here.