What are the other Names for this Condition? (Also known as/Synonyms)

• AML with Other Defined Genetic Alterations

What is Acute Myeloid Leukemia with Other Defined Genetic Alterations? (Definition/Background Information)

• Acute Myeloid Leukemia with Other Defined Genetic Alterations refers to specific acute myeloid leukemia (AML) subtypes characterized by distinct chromosomal abnormalities or genetic mutations.
• The newly proposed category of Acute Myeloid Leukemia with Other Defined Genetic Alterations includes emerging or provisional AML subtypes characterized by distinct genetic changes and associated clinicopathologic features. These subtypes include:
  • Acute Myeloid Leukemia with CBFA2T3::GLIS2: inv(16)(p13q24)
  • Acute Myeloid Leukemia with KAT6A::CREBBP: t(8;16)(p11.2;p13.3)
  • Acute Myeloid Leukemia with FUS::ERG: t(16;21)(p11;q22)
  • Acute Myeloid Leukemia with MNX1::ETV6: t(7;12)(q36;p13)
  • Acute Myeloid Leukemia with NPM1::MLF1: t(3;5)(q25;q35)
  • Acute Myeloid Leukemia with RARG (12q13) fusions (very rare cases)
• Unlike some well-known fusion genes in AML, such as PML-RARA or RUNX1-RUNX1T1, these alterations involve unique genetic changes that significantly affect disease prognosis and treatment strategies.
• This subtype of AML is identified through specialized genetic testing, including cytogenetic analysis and molecular profiling, which helps determine the presence of specific genetic alterations in leukemia cells.
• Understanding these genetic alterations is crucial as they contribute to the development, progression, and behavior of leukemia cells, ultimately influencing the overall clinical management of the disease.

Who gets Acute Myeloid Leukemia with Other Defined Genetic Alterations? (Age and Sex Distribution)

• Acute Myeloid Leukemia (AML) with Other Defined Genetic Alterations can occur in individuals of various age groups, but it is more commonly diagnosed in adults than in children.
• The median age at diagnosis for this subtype of AML varies depending on the specific genetic alteration but generally falls between 50 to 60 years old.
• There is no significant predilection for a specific sex; both males and females can be affected by AML with other defined genetic alterations.
• In pediatric cases of AML, these specific genetic alterations may be less common compared to adult-onset AML, where they are more frequently observed.

What are the Risk Factors for Acute Myeloid Leukemia with Other Defined Genetic Alterations? (Predisposing Factors)

The risk factors for Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Exposure to certain environmental toxins or chemicals, such as benzene, radiation, and certain chemotherapy drugs, can increase the risk of developing AML with specific genetic alterations.
• Previous treatment for other cancers, particularly with radiation therapy or certain chemotherapeutic agents, may predispose individuals to develop secondary AML with defined genetic alterations.
• Certain genetic syndromes, such as Fanconi anemia, Bloom syndrome, or Li-Fraumeni syndrome, are associated with an increased risk of developing AML with specific genetic alterations.
• Age is a significant risk factor, as AML with defined genetic alterations is more commonly diagnosed in older adults, especially those over the age of 50.
• Smoking tobacco has been linked to an increased risk of developing AML, including specific genetic subtypes.
• Inherited genetic predispositions or familial history of hematologic malignancies can also contribute to the risk of developing AML with defined genetic alterations

It is important to note that having a risk factor does not mean that one will get the condition. A risk factor increases one's chances of getting a condition compared to an individual without the risk factors. Some risk factors are more important than others.

Also, not having a risk factor does not mean that an individual will not get the condition. It is always important to discuss the effect of risk factors with your healthcare provider.

What are the Causes of Acute Myeloid Leukemia with Other Defined Genetic Alterations? (Etiology)

The causes of Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Genetic Mutations:
  • Chromosomal Translocations: Involve the rearrangement of genetic material between different chromosomes, leading to fusion genes that drive leukemia development. Examples include inv(3)(q21q26.2), inv(16)(p13.1q22), t(8;21)(q22;q22.1), and others.
  • Point Mutations: Alterations in specific genes, such as FLT3, DNMT3A, IDH1, and IDH2, can disrupt normal cell function and contribute to leukemia development.
• Environmental Exposures:
  • Carcinogenic Substances: Exposure to substances like benzene, a known occupational carcinogen, can cause DNA damage and increase the risk of developing AML with defined genetic alterations.
  • Radiation: Ionizing radiation, either from medical procedures or environmental sources, can induce genetic mutations that promote leukemia development.
• Previous Cancer Treatments: Certain chemotherapy agents, such as alkylating agents (e.g., cyclophosphamide) and topoisomerase II inhibitors (e.g., etoposide), can damage DNA and increase the risk of secondary AML with defined genetic alterations.
• Inherited Syndromes: Individuals with genetic syndromes like Fanconi anemia, Bloom syndrome, Li-Fraumeni syndrome, Down syndrome, and others have an elevated risk of developing AML with specific genetic alterations.
• Age: Advancing age is a significant risk factor for AML with defined genetic alterations, particularly in older adults over the age of 50.
• Smoking: Tobacco smoking has been associated with an increased risk of developing AML, including specific genetic subtypes associated with defined genetic alterations.

What are the Signs and Symptoms of Acute Myeloid Leukemia with Other Defined Genetic Alterations?

The signs and symptoms of Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Fatigue and Weakness: Persistent fatigue and weakness that do not improve with rest are common symptoms of AML with defined genetic alterations.
• Shortness of Breath: Difficulty breathing, especially during physical activity or exertion, can occur due to anemia, which results from decreased red blood cell production.
• Easy Bruising and Bleeding: AML with defined genetic alterations can lead to low platelet counts, causing easy bruising, bleeding gums, frequent nosebleeds, and prolonged bleeding from minor injuries.
• Frequent Infections: Decreased white blood cell counts in AML can weaken the immune system, making individuals more susceptible to infections that may be recurrent or severe.
• Bone Pain: Leukemia cells can infiltrate the bone marrow, leading to bone pain, especially in the ribs, sternum, and long bones like the legs.
• Enlarged Liver or Spleen: AML with defined genetic alterations may cause hepatomegaly (enlarged liver) or splenomegaly (enlarged spleen), which can be felt as abdominal discomfort or fullness.
• Weight Loss: Unintentional weight loss can occur in individuals with AML due to a combination of factors such as decreased appetite, metabolic changes, and the disease's impact on overall health.
• Fever and Night Sweats: Some individuals with AML may experience fever, night sweats, and general malaise, common symptoms of many hematologic malignancies.
• Swollen Lymph Nodes: In some cases, lymphadenopathy (swollen lymph nodes) may be present, particularly if the leukemia cells have spread to lymphatic tissues.
• Neurological Symptoms: Rarely, AML with defined genetic alterations can cause neurological symptoms like headaches, confusion, seizures, or visual disturbances if leukemia cells involve the central nervous system.

How is Acute Myeloid Leukemia with Other Defined Genetic Alterations Diagnosed?

The diagnosis of Acute Myeloid Leukemia with Other Defined Genetic Alterations involves a combination of the following:

• Blood Tests: Initial diagnosis often begins with blood tests, including a complete blood count        (CBC) to assess levels of red blood cells, white blood cells, and platelets. Abnormalities such as low red blood cell counts (anemia), low platelet counts (thrombocytopenia), and abnormal white blood cell counts may indicate leukemia.
• Bone Marrow Aspiration and Biopsy: A definitive diagnosis of AML with defined genetic alterations requires bone marrow aspiration and biopsy. During this procedure, a small sample of bone marrow and bone tissue is collected and examined under a microscope for the presence of leukemia cells and specific genetic abnormalities.
• Cytogenetic Analysis: Specialized testing, such as cytogenetic analysis or fluorescence in situ hybridization (FISH), is performed on bone marrow samples to identify chromosomal abnormalities and genetic mutations characteristic of AML with defined genetic alterations.
• Molecular Testing: Molecular testing, including polymerase chain reaction (PCR) and next-generation sequencing (NGS), is used to detect specific gene mutations associated with AML, such as FLT3, NPM1, DNMT3A, IDH1, IDH2, and others. These tests help determine the genetic profile of the leukemia cells, guiding treatment decisions and predicting prognosis.
• Immunophenotyping: Flow cytometry and immunohistochemistry are used for immunophenotyping, which involves identifying cell surface markers on leukemia cells to classify the subtype of AML and determine its aggressiveness.
• Lumbar Puncture: In some cases, a lumbar puncture (spinal tap) may be performed to evaluate for the presence of leukemia cells in the cerebrospinal fluid, especially if there are neurological symptoms or concerns about central nervous system involvement.

Many clinical conditions may have similar signs and symptoms. Your healthcare provider may perform additional tests to rule out other clinical conditions to arrive at a definitive diagnosis.

What are the possible Complications of Acute Myeloid Leukemia with Other Defined Genetic Alterations?

The possible complications of Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Infections: Due to compromised immune function, individuals with AML with defined genetic alterations are at increased risk of developing severe infections, which can be life-threatening if not promptly treated.
• Bleeding Disorders: Low platelet counts (thrombocytopenia) in AML can lead to bleeding disorders, resulting in excessive bleeding from minor cuts or bruises, nosebleeds, gum bleeding, and internal bleeding in severe cases.
• Anemia: Reduced red blood cell production (anemia) can cause fatigue, weakness, shortness of breath, and decreased oxygen delivery to tissues, affecting overall well-being and quality of life.
• Organ Dysfunction: Infiltration of leukemia cells into organs such as the liver, spleen, lungs, and kidneys can lead to organ dysfunction, manifesting as hepatomegaly, splenomegaly, respiratory distress, and renal impairment.
• Coagulopathies: Disseminated intravascular coagulation (DIC) and other coagulopathies may occur in AML with defined genetic alterations, causing abnormal blood clotting and potential thrombotic or bleeding complications.
• Tumor Lysis Syndrome: Rapid destruction of leukemia cells during treatment can release large amounts of cellular contents into the bloodstream, leading to metabolic imbalances such as hyperuricemia, hyperkalemia, hyperphosphatemia, and hypocalcemia. If not managed appropriately, these can result in kidney injury and cardiac arrhythmias.
• Neurological Complications: In rare cases, AML with defined genetic alterations may involve the central nervous system, leading to neurological complications such as headaches, seizures, confusion, and visual disturbances.
• Secondary Cancers: Certain chemotherapy regimens and radiation therapy used to treat AML can increase the risk of developing secondary cancers in the future, necessitating long-term monitoring and follow-up care.

How is Acute Myeloid Leukemia with Other Defined Genetic Alterations Treated?

The treatment measures for Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Chemotherapy:
  • Induction Therapy: The primary treatment approach for AML with defined genetic alterations involves induction chemotherapy, typically using a combination of cytarabine and an anthracycline (e.g., daunorubicin or idarubicin). This aims to induce remission by eliminating leukemia cells from the bone marrow and bloodstream.
  • Consolidation Therapy: Following induction, consolidation chemotherapy may be administered to eradicate residual leukemia cells further and reduce the risk of relapse.
• Targeted Therapy:
  • FLT3 Inhibitors: In cases where the leukemia cells harbor FLT3 mutations, targeted therapy with FLT3 inhibitors such as midostaurin or gilteritinib may be used to specifically target and inhibit the activity of mutated FLT3 proteins.
  • IDH Inhibitors: For AML with IDH1 or IDH2 mutations, targeted inhibitors like ivosidenib or enasidenib can be employed to block the abnormal IDH enzyme and disrupt leukemia cell growth.
• Stem Cell Transplantation: Allogeneic hematopoietic stem cell transplantation (HSCT) may be recommended for eligible patients, especially in cases of high-risk or relapsed AML with defined genetic alterations. This involves replacing diseased bone marrow with healthy donor stem cells to restore normal blood cell production.
• Supportive Care:
  • Blood Transfusions: Red blood cell and platelet transfusions may be necessary to manage anemia and thrombocytopenia.
  • Growth Factors: Administration of growth factors such as erythropoietin and granulocyte colony-stimulating factor (G-CSF) can stimulate red blood cell and white blood cell production, aiding in recovery from chemotherapy-induced cytopenias.
  • Antibiotic and Antifungal Prophylaxis: Prophylactic use of antibiotics and antifungal agents may be recommended to prevent infections during periods of neutropenia.
• Symptom Management: Comprehensive symptom management and supportive care, including pain management, nutritional support, and psychosocial interventions, are integral components of AML treatment to optimize quality of life and overall well-being.
• Clinical Trials: Participation in clinical trials evaluating novel therapies, immunotherapy approaches, or targeted agents specific to the patient's genetic profile may be considered for eligible individuals, offering access to cutting-edge treatments and potential advancements in AML management.

How can Acute Myeloid Leukemia with Other Defined Genetic Alterations be Prevented?

The preventive measures for Acute Myeloid Leukemia with Other Defined Genetic Alterations include:

• Avoiding Known Risk Factors:
  • Minimize Exposure to Carcinogens: Limit exposure to environmental carcinogens such as benzene, ionizing radiation, and tobacco smoke, which are associated with an increased risk of developing AML with specific genetic alterations.
  • Occupational Safety: Practice workplace safety measures to reduce exposure to chemicals and substances known to be carcinogenic, especially in industries where there is a higher risk of exposure.
• Genetic Counseling and Testing:
  • Genetic Screening: Individuals with a family history of hematologic malignancies or known genetic syndromes associated with AML should consider genetic counseling and testing to identify potential genetic predispositions and take preventive measures accordingly.
  • Targeted Monitoring: Regular monitoring and surveillance for individuals with known genetic mutations associated with AML, such as FLT3, NPM1, and others, can help detect any early signs of leukemia development and facilitate timely intervention.
• Healthy Lifestyle Practices:
  • Balanced Diet: Maintain a healthy and balanced diet rich in fruits, vegetables, whole grains, and lean proteins to support overall well-being and immune function.
  • Regular Exercise: Engage in regular physical activity and exercise to promote cardiovascular health, maintain a healthy weight, and improve overall fitness levels.
  • Smoking Cessation: Quitting smoking and avoiding exposure to secondhand smoke can significantly reduce the risk of developing AML and other smoking-related cancers.
• Post-Cancer Treatment Monitoring: Patients undergoing previous cancer treatments, particularly those associated with increased AML risk (e.g., radiation therapy, certain chemotherapy agents), should undergo regular medical follow-up and monitoring for potential late effects or secondary cancers.
• Genetic Counseling for Survivors: Cancer survivors should receive genetic counseling and long-term follow-up care to address any potential genetic predispositions, monitor for late effects of treatment, and implement preventive strategies.
• Occupational Safety Measures: Healthcare Workers: Healthcare professionals exposed to chemotherapy agents or other hazardous substances should adhere to strict safety protocols, use personal protective equipment (PPE), and follow established guidelines to minimize occupational risks.

What is the Prognosis of Acute Myeloid Leukemia with Other Defined Genetic Alterations? (Outcomes/Resolutions)

The prognosis for Acute Myeloid Leukemia with Other Defined Genetic Alterations depends on the following :

• Response to Treatment:
  • Complete Remission (CR): Some individuals with AML and defined genetic alterations achieve complete remission, where no evidence of leukemia is detected in bone marrow samples after treatment. CR is associated with better outcomes and a lower risk of relapse.
  • Partial Remission (PR): In cases where residual leukemia cells are present but reduced compared to pre-treatment levels, partial remission may be achieved. PR may precede complete remission or indicate a response to treatment that requires further consolidation therapy.
• Relapse Rates:
  • Relapse after achieving remission is a significant concern in AML with defined genetic alterations. The risk of relapse varies depending on factors such as the specific genetic mutation, response to initial treatment, and patient characteristics.
  • High-risk genetic subtypes, such as FLT3-ITD mutations or adverse cytogenetics, are associated with a higher likelihood of relapse, necessitating close monitoring and potential consideration of post-remission therapies like stem cell transplantation.
• Survival Rates:
  • Overall Survival (OS): The overall survival rates for AML with defined genetic alterations vary widely depending on factors such as age, genetic subtype, response to treatment, and presence of coexisting medical conditions.
  • Favorable genetic subtypes, such as AML with inv(16) or t(8;21) mutations, typically have better outcomes and higher survival rates compared to high-risk genetic subtypes like AML with complex karyotype or adverse cytogenetics.
• Post-Remission Therapies:
  • Stem Cell Transplantation: Allogeneic hematopoietic stem cell transplantation (HSCT) may be considered for eligible patients in first remission, especially those with high-risk genetic features or a history of relapse. HSCT aims to achieve long-term disease control and improve survival outcomes.
  • Maintenance Therapy: Some patients may benefit from maintenance therapy with targeted agents or low-dose chemotherapy to prolong remission and reduce the risk of relapse.
• Risk Stratification:
  • Risk-adapted treatment strategies based on genetic and cytogenetic risk stratification play a crucial role in determining the prognosis and guiding treatment decisions in AML with defined genetic alterations.
  • Close collaboration between hematologists, oncologists, and molecular geneticists is essential to accurately assess prognosis, tailor treatment plans, and optimize long-term outcomes for individuals with AML and specific genetic mutations.

Additional and Relevant Useful Information for Acute Myeloid Leukemia with Other Defined Genetic Alterations:

Minimal Residual Disease (MRD) Monitoring: In AML with Other Defined Genetic Alterations, monitoring for minimal residual disease (MRD) after treatment can provide valuable prognostic information. MRD refers to the small number of leukemia cells that may remain undetectable by standard tests but can potentially lead to relapse. MRD monitoring using sensitive molecular techniques, such as quantitative polymerase chain reaction (qPCR) or next-generation sequencing (NGS), allows for early residual disease detection and timely intervention if necessary.