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

• Acute Myeloid Leukemia with MLL Gene Rearrangement
• AML with KMT2A Rearrangement
• KMT2A-Rearranged AML

What is Acute Myeloid Leukemia with KMT2A Rearrangement? (Definition/Background Information)

• Acute Myeloid Leukemia with KMT2A Rearrangement, also known as MLL gene rearrangement, is a subtype of acute myeloid leukemia (AML). It is characterized by specific genetic alterations involving the KMT2A gene, formerly known as the MLL gene, located on chromosome 11q23
• This rearrangement leads to the fusion of the KMT2A gene with various partner genes, resulting in abnormal gene expression and disrupted cellular functions. The KMT2A gene plays a crucial role in regulating cell growth and differentiation, and its rearrangement is associated with the development of AML
• KMT2A rearrangements are common in pediatric AML cases but can also occur in adults. Genetic predisposition, exposure to certain environmental factors, and prior treatment with chemotherapy or radiation therapy may contribute to its development in some individuals
• Acute Myeloid Leukemia with KMT2A Rearrangement typically presents with signs and symptoms similar to other types of AML. These can include fatigue, weakness, fever, frequent infections, easy bruising or bleeding, shortness of breath, and bone pain. Additionally, individuals may experience symptoms related to the infiltration of leukemia cells into various organs, such as liver or spleen enlargement
• A diagnosis of this AML subtype involves a combination of clinical evaluation, laboratory tests, and genetic analysis. Blood tests may reveal abnormal levels of white blood cells, red blood cells, platelets, and leukemia cells. Genetic testing, such as fluorescence in situ hybridization (FISH) or polymerase chain reaction (PCR), is used to identify the specific KMT2A rearrangement and other genetic abnormalities that may influence prognosis and treatment decisions
• The complications of Acute Myeloid Leukemia with KMT2A Rearrangement can include severe infections due to compromised immune function, bleeding disorders resulting from low platelet counts, and anemia leading to fatigue and weakness. Additionally, there is an increased risk of developing treatment-related complications, such as chemotherapy-related side effects or organ toxicities
• The treatment of Acute Myeloid Leukemia with KMT2A rearrangement typically involves intensive chemotherapy regimens aimed at achieving disease remission. Depending on factors such as the patient's age, overall health, and genetic profile of the leukemia cells, additional treatments such as stem cell transplantation may be considered
• The poor prognosis associated with this subtype of AML also presents a significant complication, necessitating aggressive treatment approaches and close monitoring for disease recurrence. Targeted therapies and experimental treatments may also be explored, particularly for high-risk diseases or those who do not respond well to standard treatments

Who gets Acute Myeloid Leukemia with KMT2A Rearrangement? (Age and Sex Distribution)

• Acute Myeloid Leukemia (AML) with KMT2A Rearrangement can occur in children and adults, but it is more commonly observed in pediatric populations
  • In children, it typically presents in early childhood, with a peak incidence between 1 and 3 years of age
  • This subtype of AML accounts for a significant proportion of pediatric leukemia cases, particularly in infants and young children
• In adults, AML with KMT2A Rearrangement is less common but can still occur, especially in younger adults
• No significant gender predilection is observed, and both males and females can be affected equally
• Worldwide, individuals across all racial and ethnic groups are prone to this malignancy

What are the Risk Factors for Acute Myeloid Leukemia with KMT2A Rearrangement? (Predisposing Factors)

The risk Factors for Acute Myeloid Leukemia with KMT2A Rearrangement include:

• Genetic predisposition: Individuals with certain genetic syndromes, such as Down syndrome (Trisomy 21), Li-Fraumeni syndrome, and Fanconi anemia, are at an increased risk
• Prior exposure to chemotherapy or radiation therapy: Patients who have undergone previous treatments for other cancers, such as chemotherapy or radiation therapy, may be at a higher risk of developing secondary AML with KMT2A Rearrangement
• Environmental factors: Exposure to environmental toxins, such as benzene, certain chemicals, and ionizing radiation, has been linked to an increased risk of developing AML, including cases with KMT2A rearrangement
• Age: While AML with KMT2A Rearrangement can occur at any age, it is more commonly observed in infants and young children
• Family history: Individuals with a family history of leukemia or other hematological disorders may have a slightly higher risk of developing AML with KMT2A Rearrangement, although most cases occur sporadically
• Genetic mutations: Specific genetic mutations, such as genes involved in DNA repair or cell cycle regulation, may predispose individuals to this condition

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 KMT2A Rearrangement? (Etiology)

The causes of Acute Myeloid Leukemia (AML) with KMT2A Rearrangement include:

• Genetic mutations: AML with KMT2A Rearrangement is primarily caused by specific genetic mutations involving the KMT2A gene, earlier termed the MLL gene
• Chromosomal translocations: The most common cause of KMT2A rearrangement in AML is chromosomal translocations, where a portion of the KMT2A gene on chromosome 11q23 fuses with a partner gene from another chromosome
• Fusion proteins: These chromosomal translocations result in the formation of fusion proteins that disrupt normal gene expression and cellular functions, leading to uncontrolled proliferation of immature myeloid cells characteristic of AML
• Partner genes: The partner genes involved in the translocation with KMT2A can vary, and different fusion proteins may have different oncogenic properties, influencing the clinical behavior and prognosis of AML with KMT2A Rearrangement
• Loss of regulatory mechanisms: The fusion proteins generated by KMT2A rearrangement interfere with normal regulatory mechanisms that control cell growth, differentiation, and apoptosis, contributing to leukemogenesis

While genetic mutations and chromosomal translocations are the primary causes of AML with KMT2A Rearrangement, secondary factors such as environmental exposures, prior chemotherapy or radiation therapy, and underlying genetic predispositions may also play a role in disease development in some cases.

What are the Signs and Symptoms of Acute Myeloid Leukemia with KMT2A Rearrangement?

The signs and symptoms of Acute Myeloid Leukemia with KMT2A Rearrangement include:

General signs and symptoms:

• Fatigue and weakness: Due to reduced red blood cell production (anemia) and increased metabolic demands of leukemia cells
• Fever and infections: Resulting from suppressed immune function due to abnormal white blood cell production
• Easy bruising and bleeding: Low platelet counts (thrombocytopenia) lead to impaired blood clotting
• Bone pain results from infiltrating leukemia cells into bone marrow and bones

Specific signs and symptoms related to leukemic infiltration:

• Enlarged lymph nodes, spleen, or liver: These are caused by the accumulation of leukemia cells in these organs
• Respiratory symptoms: If leukemia cells infiltrate the lungs, they can cause shortness of breath, coughing, or chest pain
• Neurological symptoms: Such as headaches, confusion, or seizures if leukemia cells involve the central nervous system (CNS)
• Skin manifestations: These include petechiae (small red spots), ecchymosis (bruises), or leukemic cutis (skin infiltrates) due to abnormal bleeding or skin involvement by leukemia cells

Other possible signs and symptoms include:

• Weight loss
• Loss of appetite
• Night sweats
• Paleness (pallor) of the skin
• Abdominal discomfort or fullness
• Joint pain or swelling (arthralgia or arthritis)

It is important to note that the specific signs and symptoms can vary among individuals. Some individuals may be asymptomatic initially, with the disease detected during routine blood tests or investigations for other health issues.

How is Acute Myeloid Leukemia with KMT2A Rearrangement Diagnosed?

The diagnosis of Acute Myeloid Leukemia (AML) with KMT2A Rearrangement involves a combination of the following:

• Blood tests:
  • Complete blood count (CBC) test: A CBC assesses levels of red blood cells, white blood cells, and platelets. In AML, abnormalities such as low red blood cells (anemia), low platelets (thrombocytopenia), and abnormal white blood cell counts (leukocytosis or leukopenia) may be observed
  • Peripheral blood smear exam: A microscopic examination of blood cells can reveal abnormal cell morphology, such as blasts (immature cells), characteristic of leukemia
  • Blood chemistry tests evaluate organ function and electrolyte levels, providing additional information about the patient's health
• Bone marrow biopsy and aspiration:
  • Bone marrow aspiration involves extracting a sample of bone marrow fluid and cells using a needle
  • Bone marrow biopsy involves taking a small core of bone marrow tissue for further examination

These procedures help confirm the diagnosis of acute myeloid leukemia, assess the percentage of blasts in the bone marrow (blast percentage), and detect genetic abnormalities, including KMT2A rearrangement, through cytogenetic and molecular analyses.

• Cytogenetic and molecular testing:
  • Karyotyping: Chromosome analysis (karyotyping) of bone marrow cells is performed to identify chromosomal abnormalities, including translocations involving the KMT2A gene
  • Fluorescence in situ hybridization (FISH): FISH is a technique used to detect specific genetic abnormalities, such as KMT2A rearrangement, by labeling and visualizing specific DNA sequences in cells
  • Polymerase chain reaction (PCR): PCR-based assays can detect fusion genes resulting from KMT2A rearrangement, providing molecular confirmation of the genetic abnormality
• Immunophenotyping:
  • Flow cytometry analysis of bone marrow or peripheral blood samples is used to identify and characterize leukemia cells based on their cell surface markers and immunological features
  • Immunophenotyping helps classify AML subtypes and determine leukemia cells' differentiation stage
• Imaging studies: Chest X-ray, CT scan, or MRI scan may be performed to evaluate the extent of organ involvement, such as enlarged lymph nodes, spleen, or liver, and detect any leukemic infiltrates in organs like the lungs or central nervous system (CNS)

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 KMT2A Rearrangement?

The possible Complications of Acute Myeloid Leukemia with KMT2A Rearrangement include:

• Complications related to disease progression:
  • Bone marrow failure: As leukemia cells proliferate, normal bone marrow function may be compromised, reducing the production of red blood cells, white blood cells, and platelets
  • Increased risk of infections: The suppression of normal white blood cell function and decreased immune response can make patients more susceptible to infections, including bacterial, viral, and fungal infections
  • Bleeding disorders: Low platelet counts (thrombocytopenia) can result in bleeding tendencies, leading to petechiae, ecchymosis, nosebleeds, and gastrointestinal bleeding
• Organ infiltration and dysfunction:
  • Central nervous system (CNS) involvement: Leukemia cells can infiltrate the CNS, leading to neurological complications such as headaches, seizures, confusion, and cranial nerve palsies
  • Hepatosplenomegaly: Enlargement of the liver (hepatomegaly) and spleen (splenomegaly) due to leukemic infiltration can cause abdominal discomfort, early satiety, and potential complications like portal hypertension
  • Respiratory complications: Leukemia cells infiltrating the lungs can cause respiratory distress, coughing, chest pain, and increased susceptibility to respiratory infections
• Treatment-related complications:
  • Chemotherapy-related side effects: Intensive chemotherapy regimens used to treat AML can lead to various side effects, including nausea, vomiting, hair loss, fatigue, mucositis, and increased risk of infections
  • Bone marrow suppression: Chemotherapy can further suppress bone marrow function, leading to prolonged cytopenia and increased susceptibility to infections and bleeding
  • Secondary malignancies: Some patients may develop secondary cancers, such as therapy-related myelodysplastic syndrome (t-MDS) or therapy-related acute myeloid leukemia (t-AML), as a complication of previous treatments
• Psychosocial and quality of life issues:
  • Emotional and psychological impact: Dealing with a diagnosis of AML and undergoing intensive treatments can cause significant emotional distress, anxiety, depression, and changes in quality of life for patients and their families
  • Financial burden: The costs associated with AML treatment, including hospitalizations, medications, and supportive care, can create financial strain for patients and may impact access to necessary healthcare services

How is Acute Myeloid Leukemia with KMT2A Rearrangement Treated?

The treatment measures for Acute Myeloid Leukemia (AML) with KMT2A Rearrangement  may involve:

• Chemotherapy:
  • Induction therapy: The primary treatment approach for AML with KMT2A Rearrangement involves induction chemotherapy, which aims to achieve complete remission by reducing the number of leukemia cells in the bone marrow and peripheral blood
  • Standard regimens: Chemotherapy protocols commonly used include combinations of cytarabine and anthracyclines (e.g., daunorubicin or idarubicin), often referred to as 7+3 regimen
  • High-dose cytarabine consolidation: After achieving remission, patients may undergo consolidation therapy with high-dose cytarabine to further eliminate residual leukemia cells and prevent relapse
• Stem cell transplantation (SCT):
  • Allogeneic stem cell transplantation: Allogeneic SCT may be considered consolidation therapy for eligible patients, especially those with high-risk features or relapsed disease
  • Donor selection: A suitable donor (usually a matched sibling or unrelated donor) is identified for SCT, and the patient undergoes conditioning therapy followed by infusion of donor stem cells to replace the diseased bone marrow with healthy cells
• Targeted therapy:
  • FLT3 inhibitors: Patients with FLT3 mutations, often co-occurring with KMT2A rearrangement, may benefit from targeted therapies such as FLT3 inhibitors (e.g., midostaurin and gilteritinib) either alone or in combination with chemotherapy
  • Other targeted agents: Investigational drugs targeting specific molecular abnormalities associated with AML, such as IDH inhibitors (e.g., ivosidenib and enasidenib) or venetoclax (BCL-2 inhibitor), may also be considered in certain cases
• Supportive care:
  • Hematopoietic growth factors: Growth factors such as granulocyte colony-stimulating factor (G-CSF) or erythropoiesis-stimulating agents (ESA) may be administered to support blood cell production during and after chemotherapy
  • Transfusion support: Red blood cell transfusions, platelet transfusions, and possibly granulocyte transfusions may be necessary to manage cytopenias and bleeding risks
  • Infection prevention and treatment: Given patients' increased susceptibility to infections during treatment, prophylactic antibiotics, antifungal agents, and antiviral medications are used to prevent and treat infections

Clinical trials: Eligible patients may be offered participation in clinical trials exploring novel treatment approaches, including new drugs, immunotherapy, and targeted agents, as part of their treatment plan.

Ongoing research efforts continue to identify and develop promising therapies specifically targeting the molecular pathways involved in AML with KMT2A Rearrangement, with the goal of improving treatment outcomes and reducing relapse rates.

How can Acute Myeloid Leukemia with KMT2A Rearrangement be Prevented?

No specific measures or strategies are known to prevent Acute Myeloid Leukemia with KMT2A rearrangement because its development is primarily attributed to genetic mutations and chromosomal translocations that occur spontaneously. However, some general recommendations and considerations may help reduce the risk of developing leukemia or manage the disease more effectively:

• Genetic counseling: For individuals with a family history of leukemia or known genetic syndromes associated with increased cancer risk (e.g., Down syndrome, Li-Fraumeni syndrome), genetic counseling and testing may provide valuable information about potential hereditary factors and help assess the risk of developing acute myeloid leukemia (AML) or other hematological malignancies
• Avoiding known risk factors: While specific causative factors for AML with KMT2A Rearrangement are largely unknown, avoiding exposure to known carcinogens such as benzene, ionizing radiation, and certain chemicals may reduce the risk of developing leukemia
• Healthy lifestyle choices: Adopting a healthy lifestyle, including maintaining a balanced diet, regular exercise, avoiding tobacco and excessive alcohol consumption, and managing stress effectively, can contribute to overall well-being and potentially reduce the risk of developing certain types of cancer, although their direct impact on AML prevention is not well established
• Monitoring and early detection: Regular medical check-ups, screenings, and monitoring of blood cell counts may help detect any abnormalities early, including signs of leukemia or other blood disorders. Early detection can lead to timely intervention and appropriate management, improving treatment outcomes and prognosis

While not a preventive measure per se, participation in clinical trials evaluating new treatments, targeted therapies, and immunotherapies for AML with KMT2A Rearrangement can contribute to advancing medical knowledge, improving treatment options, and potentially enhancing future patient outcomes.

What is the Prognosis of Acute Myeloid Leukemia with KMT2A Rearrangement? (Outcomes/Resolutions)

The prognosis of Acute Myeloid Leukemia (AML) with KMT2A rearrangement can vary widely depending on several factors, including patient age, overall health status, specific genetic abnormalities, response to treatment, and the presence of additional molecular or cytogenetic abnormalities.

• Pediatric vs. adult patients:
  • In pediatric patients, AML with KMT2A Rearrangement is often associated with a relatively poor prognosis compared to other AML subtypes, primarily due to aggressive disease behavior, higher rates of relapse, and challenges in achieving long-term remission
  • In adult patients, AML with KMT2A Rearrangement may also have a less favorable prognosis, although outcomes can vary significantly based on factors such as cytogenetic risk stratification, presence of co-mutations (e.g., FLT3 mutations), and response to therapy
• Impact of cytogenetic and molecular features:
  • Additional cytogenetic abnormalities or molecular mutations, such as FLT3-ITD, NPM1, or CEBPA mutations, can influence the prognosis of AML with KMT2A Rearrangement, with certain combinations associated with more favorable or adverse outcomes
  • High-risk features, such as complex karyotype, monosomal karyotype, or FLT3-ITD mutations with high allelic ratio, are often associated with poorer prognosis and higher treatment resistance and relapse rates
• Response to treatment:
  • The initial response to induction chemotherapy, as indicated by the achievement of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi), is a critical determinant of prognosis
  • Patients who achieve CR or CRi after induction therapy have a better prognosis and may proceed to consolidation therapy or stem cell transplantation, which can further improve outcomes and reduce the risk of relapse
• Relapse rates and survival outcomes:
  • Relapse rates are relatively high in AML with KMT2A Rearrangement, particularly in pediatric patients, leading to lower overall survival rates compared to other AML subtypes.
  • Despite advancements in treatment strategies, including targeted therapies and stem cell transplantation, the prognosis for relapsed or refractory AML with KMT2A Rearrangement remains challenging, emphasizing the need for novel therapeutic approaches and personalized treatment strategies

Individuals with AML and KMT2A Rearrangement often present with aggressive disease and may require intensive treatment strategies. Understanding the molecular mechanisms underlying KMT2A rearrangements is essential for developing targeted therapies and improving outcomes for patients with this subtype of AML.

Additional and Relevant Useful Information for Acute Myeloid Leukemia with KMT2A Rearrangement:

• Treatment challenges: The AML-KMT2A Rearrangement poses treatment challenges due to its aggressive nature and, in some cases, resistance to standard chemotherapy regimens
• Targeted therapies, such as inhibitors of FLT3 or other pathways implicated in leukemogenesis, are being investigated to improve treatment outcomes

Risk of secondary malignancies: Patients with AML-KMT2A Rearrangement, especially those undergoing intensive chemotherapy and stem cell transplantation, risk developing secondary malignancies such as therapy-related myeloid neoplasms (t-MNs)