Key Features:

Origin: AML develops from the myeloid lineage of blood cells, which normally produce red blood cells, platelets, and certain types of white blood cells (like neutrophils).

Acute Nature: It progresses quickly, leading to severe symptoms in a short period.

Symptoms: Fatigue, frequent infections, easy bruising, bleeding, fever, and bone pain.

Common in Adults: While it can occur at any age, AML is more common in older adults.

Symptoms of Acute Myeloid Leukemia (AML)

The symptoms of AML occur due to the accumulation of abnormal myeloblasts in the bone marrow and their interference with the production of normal blood cells. These symptoms can develop quickly and vary in severity.

General Symptoms

• Fatigue or Weakness: Caused by anemia due to a reduced number of red blood cells.
• Fever: Often due to infections or as a result of the disease itself.
• Unexplained Weight Loss: Loss of appetite or weight without trying.

2. Symptoms Due to Low Red Blood Cells (Anemia)

• Pale Skin (pallor).
• Shortness of Breath: Even with mild physical activity.
• Dizziness or Lightheadedness.

3. Symptoms Due to Low White Blood Cells

• Frequent Infections: Infections may be severe or prolonged due to a weakened immune system.
• Slow Healing: Wounds and infections may take longer to resolve.

4. Symptoms Due to Low Platelets

• Easy Bruising: Even with minor injuries.
• Frequent Nosebleeds or bleeding gums.
• Petechiae: Small, red or purple spots under the skin caused by bleeding.
• Prolonged Bleeding: Cuts or injuries may bleed more than usual.

5. Bone and Joint Pain

• Pain in Bones or Joints: From the buildup of leukemia cells in the bone marrow.

6. Swollen or Enlarged Organs

• Swollen Lymph Nodes: Painless swelling in the neck, armpit, or groin.
• Enlarged Liver or Spleen: May cause abdominal swelling or discomfort.

7. Bleeding or Clotting Issues

• Heavy Menstrual Bleeding (in women).
• Unusual Bleeding: Such as blood in the urine or stools.

8. Rare Symptoms

• Gum Swelling or Bleeding: Due to infiltration of leukemia cells.
• Skin Rashes or Lesions: Leukemia cutis, where abnormal cells invade the skin.
• Neurological Symptoms: Headaches, seizures, or confusion (if the central nervous system is involved).

Importance of Early Detection

Symptoms of AML can mimic other conditions. Prompt medical evaluation, including blood tests and bone marrow examination, is crucial for diagnosis and initiating treatment.

TYPES OF AML

Acute Myeloid Leukemia (AML) is classified into different types based on the characteristics of the leukemia cells, the stage of development at which the cells became malignant, and specific genetic and molecular features. Understanding the type of AML helps guide treatment decisions and predict outcomes. Here’s an overview of the types of AML:

1. Classification Based on WHO Criteria

The World Health Organization (WHO) classifies AML into several categories based on cytogenetics (chromosomal abnormalities), molecular mutations, and clinical features:

1. AML with Recurrent Genetic Abnormalities

This category includes subtypes defined by specific genetic changes, often associated with prognosis:

• t(8;21)(q22;q22.1): Involves the RUNX1-RUNX1T1 fusion gene; usually associated with favorable outcomes.
• Inv(16)(p13.1q22) or t(16;16)(p13.1;q22): Involves CBFB-MYH11; often favorable prognosis.
• Acute Promyelocytic Leukemia (APL): Defined by t(15;17)(q22;q12), involving the PML-RARA fusion gene; requires targeted treatment with all-trans retinoic acid (ATRA) and arsenic trioxide.
• t(9;11)(p21.3;q23.3): Involves KMT2A (MLL) rearrangements; intermediate prognosis.
• Other rare translocations (e.g., t(6;9), inv(3)).

1. AML with Myelodysplasia-Related Changes

• Occurs in patients with a history of myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN).
• Associated with poor prognosis due to complex genetic abnormalities.

1. Therapy-Related AML

• Develops after chemotherapy or radiation for a previous cancer.
• Often involves genetic mutations or chromosomal abnormalities.
• Prognosis is generally poor.

1. AML Not Otherwise Specified (NOS)

• Cases that do not fit into the other categories.
• Subtypes are classified based on the cell type involved (e.g., myeloblastic, monocytic, or erythroid leukemia).

2. Classification Based on FAB Criteria

The French-American-British (FAB) system categorizes AML into 8 subtypes (M0 to M7) based on the type of cell and its level of maturity:

• M0: Undifferentiated AML (poorly differentiated myeloblasts).
• M1: AML with minimal maturation.
• M2: AML with maturation (common subtype).
• M3: Acute Promyelocytic Leukemia (APL).
• M4: Acute Myelomonocytic Leukemia (involves both myeloblasts and monoblasts).
• M5: Acute Monocytic Leukemia (predominantly monoblasts).
• M6: Acute Erythroid Leukemia (involves erythroid precursors).
• M7: Acute Megakaryoblastic Leukemia (involves megakaryoblasts, precursors to platelets).

3. AML with Specific Molecular Mutations

• NPM1 Mutation: Common in AML, often associated with a favorable prognosis when no other high-risk mutations are present.
• FLT3 Mutation: Affects prognosis depending on the subtype (FLT3-ITD mutation is linked to poorer outcomes; targeted therapies are available).
• CEBPA Mutation: Associated with a favorable prognosis when biallelic.

4. Other Rare Subtypes

• Myeloid Sarcoma: A solid tumor composed of leukemia cells, occurring outside the bone marrow.
• Blastic Plasmacytoid Dendritic Cell Neoplasm (BPDCN): A rare and aggressive subtype with features of AML.

Importance of Classification

The classification of AML is critical for:

1. Determining the treatment plan (e.g., chemotherapy, targeted therapy, stem cell transplant).
2. Understanding the prognosis (some subtypes respond better to treatment than others).
3. Identifying the need for specialized treatments like targeted therapies for FLT3 or APL-specific therapies.

Causes and Risk Factors of Acute Myeloid Leukemia (AML)

The exact cause of Acute Myeloid Leukemia (AML) is not fully understood, but it is known to result from mutations in the DNA of bone marrow cells that affect normal blood cell production. These mutations lead to the uncontrolled growth of immature white blood cells (myeloblasts) and impair the formation of healthy blood cells.

While AML is not always linked to specific causes, certain risk factors are associated with its development:

Causes of AML

1. Genetic Mutations:
   • AML occurs when specific genetic mutations alter the normal development and function of myeloid cells in the bone marrow.
   • These mutations may be spontaneous or triggered by environmental factors.
2. Chromosomal Abnormalities:
   • Chromosomal translocations or rearrangements (e.g., t(8;21), inv(16)) can disrupt normal gene function, leading to leukemia.
3. Clonal Hematopoiesis:
   • Age-related accumulation of mutations in hematopoietic stem cells can predispose to AML.

Risk Factors for AML

1. Genetic Predisposition

• Inherited Syndromes:
  • Down Syndrome: Increased risk of developing AML, especially the megakaryoblastic subtype.
  • Li-Fraumeni Syndrome: Caused by mutations in the TP53 gene.
  • Fanconi Anemia and Bloom Syndrome: Rare genetic disorders linked to AML.
  • Familial Platelet Disorder with Predisposition to AML.
• Family History:
  • Rarely, AML runs in families due to inherited genetic mutations.

2. Environmental Exposures

• Radiation Exposure:
  • High doses of ionizing radiation (e.g., from nuclear accidents or certain medical treatments).
• Chemical Exposure:
  • Long-term exposure to benzene (found in some industrial processes and tobacco smoke).
  • Prolonged exposure to pesticides or other toxic substances.

3. Prior Medical Treatments

• Chemotherapy:
  • Use of alkylating agents or topoisomerase II inhibitors for prior cancers increases the risk of therapy-related AML (t-AML).
• Radiation Therapy:
  • Exposure during treatment for another cancer can elevate AML risk.

4. Pre-existing Blood Disorders

• Myelodysplastic Syndromes (MDS):
  • Often progress to AML.
• Myeloproliferative Neoplasms (MPNs):
  • Disorders like polycythemia vera, essential thrombocythemia, or primary myelofibrosis can evolve into AML.
• Aplastic Anemia:
  • Chronic bone marrow disorders may increase susceptibility to AML.

5. Age and Gender

• Age:
  • AML is more common in older adults, with the median age of diagnosis being around 65–70 years.
• Gender:
  • Slightly more common in males than females.

6. Smoking

• Tobacco smoke contains benzene and other carcinogens that may increase the risk of AML.

7. Clonal Hematopoiesis of Indeterminate Potential (CHIP)

• A condition in which age-related mutations in blood stem cells accumulate, increasing the likelihood of AML.

8. Viral Infections (Rare)

• Certain viral infections, such as human T-cell leukemia virus (HTLV-1), have been loosely associated with leukemia development.

Uncontrollable vs. Controllable Risk Factors

• Uncontrollable: Genetic predisposition, family history, and age.
• Controllable: Avoiding tobacco use, minimizing exposure to harmful chemicals, and limiting unnecessary radiation exposure.

Conclusion

While some risk factors for AML, like age or genetic predisposition, cannot be changed, reducing exposure to environmental carcinogens, avoiding tobacco, and managing pre-existing blood disorders can help lower the risk. Early identification and treatment of precursor conditions, such as myelodysplastic syndrome, may also help prevent the progression to AML.

Treatment of Acute Myeloid Leukemia (AML)

The treatment of Acute Myeloid Leukemia (AML) involves eradicating leukemia cells, restoring normal blood cell production, and preventing relapse. The treatment plan depends on factors like the patient’s age, general health, subtype of AML, and genetic abnormalities. Here’s a breakdown of AML treatment strategies:

1. Phases of AML Treatment
2. Induction Therapy

• Goal: Achieve remission by destroying leukemia cells in the bone marrow and blood.
• Common Treatments:
  • Chemotherapy:
    • A standard regimen is “7+3”: 7 days of continuous infusion of cytarabine and 3 days of an anthracycline (e.g., daunorubicin or idarubicin).
    • In some cases, targeted drugs may be added.
  • Targeted Therapy (for specific mutations):
    • FLT3 Inhibitors: Midostaurin or gilteritinib (if FLT3 mutation is present).
  • Supportive Care: Includes blood transfusions, antibiotics, and growth factors to manage side effects.

1. Consolidation Therapy

• Goal: Eliminate any remaining leukemia cells to prevent relapse.
• Common Treatments:
  • High-dose cytarabine (HiDAC) is often used.
  • Stem Cell Transplant may be recommended for patients with high-risk AML or those with residual disease after induction.

1. Maintenance Therapy (Less Common in AML)

• Goal: Prolong remission in certain high-risk cases.
• Common Treatments:
  • Targeted drugs like oral azacitidine (for specific patients).

 Treatments for AML Subtypes

1. Acute Promyelocytic Leukemia (APL)

• A distinct subtype of AML caused by the t(15;17) PML-RARA mutation.
• Treatment:
  • All-Trans Retinoic Acid (ATRA): A vitamin A derivative that helps leukemia cells mature.
  • Arsenic Trioxide (ATO): Often combined with ATRA for a highly effective regimen.
  • Chemotherapy is used in high-risk APL cases.

1. Therapy-Related AML or AML with Myelodysplasia-Related Changes

• Requires more intensive treatment due to poor prognosis.
• Allogeneic stem cell transplant is often recommended.

3. Stem Cell Transplant

• Autologous Stem Cell Transplant: Uses the patient’s own stem cells (less common in AML).
• Allogeneic Stem Cell Transplant: Uses stem cells from a donor.
  • Often considered for high-risk AML or relapsed disease.

4. Targeted Therapies

• These drugs target specific genetic mutations in AML cells:
  • FLT3 Mutations: Midostaurin (Rydapt), Gilteritinib (Xospata).
  • IDH1/IDH2 Mutations: Ivosidenib (Tibsovo) for IDH1 and enasidenib (Idhifa) for IDH2.
  • BCL2 Inhibitor: Venetoclax (used in combination with low-dose chemotherapy for older adults or unfit patients).

5. Immunotherapy

• Monoclonal Antibodies:
  • Gemtuzumab ozogamicin (targets CD33): Used in some AML cases, often combined with chemotherapy.
• Immune Checkpoint Inhibitors: Being explored in clinical trials.

6. Palliative and Supportive Care

• For patients who cannot tolerate intensive treatment or stem cell transplant:
  • Low-Intensity Therapy: Hypomethylating agents like azacitidine or decitabine.
  • Symptom management with transfusions, antibiotics, and pain relief.

7. Treatment for Relapsed or Refractory AML

• Targeted Therapies: Gilteritinib (for FLT3-mutated relapsed AML) or enasidenib (for IDH2 mutations).
• Salvage Chemotherapy: Alternative regimens to induce remission.
• Stem Cell Transplant: Often considered if remission is achieved again.
• CAR-T Cell Therapy: Experimental treatment being studied in clinical trials.

8. Clinical Trials

• Patients with AML, especially those with relapsed or refractory disease, are encouraged to explore clinical trials for access to emerging therapies and novel drug combinations.

Factors Influencing Treatment Choice

• Patient Age: Older patients may receive less intensive regimens due to higher risks.
• Health Status: Pre-existing conditions may limit treatment options.
• Cytogenetics and Molecular Mutations: Guide targeted therapies and risk assessment.

Outlook

Treatment outcomes for AML have improved significantly, especially with the advent of targeted therapies and advanced transplantation techniques. Early diagnosis and a personalized treatment plan are critical for achieving the best results.

PREVENTION OF AML

Prevention of Acute Myeloid Leukemia (AML)

There is no guaranteed way to prevent Acute Myeloid Leukemia (AML) because many of its causes are not fully understood and involve uncontrollable factors like age, genetic mutations, or inherited conditions. However, reducing exposure to known risk factors and maintaining a healthy lifestyle can lower the risk.

1. Minimize Exposure to Environmental Toxins

• Avoid Benzene:
  • Limit exposure to benzene, a chemical found in industrial settings, gasoline, and cigarette smoke.
  • Follow workplace safety guidelines if handling benzene or similar chemicals.
• Limit Pesticides and Solvents: Use protective gear when handling potentially harmful substances.

2. Avoid Tobacco Use

• Smoking is a significant risk factor for AML, as it introduces carcinogens like benzene into the body.
• Quitting smoking can significantly reduce the risk of developing AML and other cancers.

3. Reduce Radiation Exposure

• Avoid unnecessary medical imaging procedures like X-rays and CT scans, especially in children and pregnant women.
• Ensure proper safety protocols if working in environments with potential radiation exposure.

4. Limit Chemotherapy Exposure

• If you have been treated for other cancers with chemotherapy drugs known to increase the risk of AML (e.g., alkylating agents or topoisomerase II inhibitors), discuss with your doctor the possibility of minimizing further exposure.

5. Manage Pre-existing Blood Disorders

• Conditions like myelodysplastic syndromes (MDS) or myeloproliferative neoplasms (MPN) can increase the risk of developing AML.
• Regular monitoring and early treatment of these disorders may reduce the risk of progression to AML.

6. Genetic Counseling

• If you have a family history of AML or an inherited disorder associated with an increased risk (e.g., Down syndrome, Li-Fraumeni syndrome, Fanconi anemia), consider genetic counseling.
• This can help identify risks and guide preventive care or early monitoring.

7. Strengthen Immune Health

• Maintain a healthy lifestyle:
  • Eat a balanced diet rich in fruits, vegetables, and whole grains.
  • Exercise regularly.
  • Avoid excessive alcohol consumption.
• A strong immune system may help the body handle genetic or environmental stressors more effectively.

8. Awareness and Early Detection

• Know the symptoms of AML, such as fatigue, bruising, frequent infections, or bleeding, and seek medical evaluation promptly if they occur.
• Routine health check-ups can help identify pre-leukemic conditions or genetic predispositions early.

9. Participate in Research or Clinical Trials

• Contributing to research studies or genetic registries can help scientists understand the causes of AML and develop preventive measures for future generations.

Conclusion

While not all cases of AML are preventable, taking steps to minimize exposure to known risk factors and maintaining overall health can reduce the likelihood of developing the disease. Early detection and management of predisposing conditions also play a vital role in prevention.

RECENT ADVANCEMENTS/RESEARCHES IN AML

Recent advancements in the treatment of Acute Myeloid Leukemia (AML) have led to the development of novel therapies and improved patient outcomes. Key developments include:

1. Targeted Therapies:

• Revumenib (Revuforj): In November 2024, the U.S. Food and Drug Administration (FDA) approved Revumenib for treating acute leukemia with KMT2A translocation, a condition found in about 10% of acute leukemia patients. Revumenib is a menin inhibitor that prevents the binding of menin to MLL, stopping the activation of proteins that foster cancer cell growth. 
• Quizartinib (Vanflyta): In July 2023, the FDA approved Quizartinib in combination with standard chemotherapies for the treatment of adult patients with newly diagnosed AML that carries a genetic mutation called FLT3-ITD. Quizartinib is the first drug designed to target the FLT3-ITD mutation, which accounts for approximately 25% of AML cases. 

2. Menin Inhibitors:

• Revumenib: Beyond its approval, Revumenib has shown promise in early-phase clinical trials, causing complete remission in about one-third of study participants with advanced AML. This class of drugs disrupts the formation of protein complexes that activate genes fueling leukemia cell development. 

3. Novel Drug Combinations:

• Venetoclax and STING Agonists: Researchers at the Walter and Eliza Hall Institute (WEHI) in Melbourne have developed a promising new treatment for AML using a combination of Venetoclax, a standard anti-cancer drug, and an emerging immunotherapy drug that activates the protein STING. This dual therapy delivers a powerful “one-two punch” to cancer cells and has been particularly effective in eradicating AML in lab tests, even in patients with mutations in the tumor suppressor protein P53. 

4. Genetic and Molecular Research:

• Genome Organization Disruption: Researchers have identified a key weakness in AML by disrupting the function of a certain protein complex that cancer cells rely on to maintain their abnormal growth. This discovery offers a promising new strategy to delay the progression of this aggressive blood cancer. 

5. Clinical Trials and Emerging Therapies:

• Ziftomenib: The Clinical Leukemia Service at Roswell Park led the first clinical trial of the experimental oral drug Ziftomenib in patients with AML. The results of the KOMET-001 study show that the drug, part of a class of targeted therapies known as menin inhibitors, produced a partial or complete response in about a third of patients, all of whom had received two or more prior therapies. 

These advancements represent a significant shift towards more targeted and individualized treatment strategies for AML, offering hope for improved survival rates and quality of life for patients.

Recent Developments in AML Treatments