Secondary Acute Myeloid Leukemia: An Overview

Introduction:

Within the vast spectrum of hematological disorders, secondary acute myeloid leukemia (sAML) emerges as an intricate and intriguing entity, commanding the undivided attention. While less pervasive than its primary counterpart, sAML brings forth distinctive intricacies in terms of diagnosis and treatment.

What Is the Difference Between Primary and Secondary Acute Myeloid Leukemia?

Primary acute myeloid leukemia (primary AML) and secondary acute myeloid leukemia (sAML) are both subtypes of acute myeloid leukemia (AML), but they differ in their underlying causes and risk factors. Here are the key differences between primary AML and sAML:

Origins and Causes:

• Primary AML: Primary AML, or de novo AML, occurs without a known pre-existing cause or underlying condition. It typically arises due to genetic mutations or changes in the bone marrow stem cells, leading to the uncontrolled proliferation of abnormal myeloid cells.

• Secondary AML: sAML, on the other hand, develops due to prior treatment or exposure to specific risk factors. It is often associated with previous chemotherapy or radiation therapy for other cancers, exposure to certain chemicals or toxins (for example., benzene), or pre-existing blood disorders.

Risk Factors:

• Primary AML: The risk factors for primary AML are primarily related to genetic predisposition and sporadic mutations. While certain genetic syndromes for example Down syndrome can increase the risk, most cases occur without a known familial or environmental cause.

• Secondary AML: The primary risk factors for sAML include exposure to cancer treatments like chemotherapy and radiation therapy and exposure to environmental toxins such as benzene. These treatments and exposures can damage the DNA within bone marrow cells, increasing the likelihood of developing sAML.

Genetic Abnormalities:

• Primary AML: Primary AML can be associated with genetic mutations and chromosomal abnormalities, such as mutations in genes like FLT3, NPM1, or TP53. The specific genetic profile can vary among patients.

• Secondary AML: sAML often exhibits distinct genetic changes or cytogenetic abnormalities associated with its secondary nature. These changes can include specific chromosomal rearrangements or mutations influenced by prior treatment or exposure.

Prognosis:

• Primary AML: The prognosis for primary AML can vary widely depending on factors like age, overall health, the specific genetic profile of the leukemia, and how quickly treatment is initiated. Some subtypes of primary AML have a more favorable outlook than others.

• Secondary AML: The prognosis for sAML can be less favorable compared to primary AML, especially if it is associated with high-risk genetic abnormalities or if the patient has other underlying health issues. However, outcomes can vary, and some individuals with sAML respond well to treatment.

What Are the Causes and Risk Factors of Secondary Acute Myeloid Leukemia?

Acute myeloid leukemia (AML) is a heterogeneous group of hematological malignancies characterized by the uncontrolled proliferation of myeloid precursor cells. When AML is a direct consequence of previous medical conditions or treatments, it is termed Secondary AML.

Previous Cancer Treatments:

• Chemotherapy: Cytotoxic chemotherapy is a cornerstone of cancer treatment, designed to kill rapidly dividing cancer cells. However, these treatments can also affect healthy cells, including hematopoietic stem cells in the bone marrow. The DNA damage caused by chemotherapy drugs can lead to mutations in these cells, potentially triggering the development of sAML.

• Radiation Therapy: Similar to chemotherapy, radiation therapy targets and destroys cancer cells. However, it can also inadvertently damage healthy bone marrow cells, increasing the risk of sAML.

Risk Groups:

• Patients with Prior Cancers: Individuals undergoing treatments for various cancers, such as lymphoma, breast cancer, or childhood leukemia, are at an elevated risk of developing sAML.

• Certain Genetic Disorders: Some inherited genetic conditions, such as Li-Fraumeni syndrome or Fanconi anemia, predispose individuals to a higher risk of developing both primary and secondary AML following cancer treatments.

Environmental and Occupational Exposures:

• Benzene Exposure: Benzene is a hazardous chemical compound found in various industrial settings, including the petrochemical and rubber industries. Prolonged exposure to benzene, either through inhalation or skin contact, is associated with an increased risk of sAML.

• Other Toxic Exposures: While benzene is a prominent example, other toxic substances, such as certain solvents, pesticides, and heavy metals, have also been linked to sAML when individuals are exposed to them over extended periods.

Risk Groups:

• Industrial Workers: Individuals employed in industries where exposure to benzene and other toxic substances is common are particularly vulnerable. This includes workers in chemical plants, refineries, and factories.

• Environmental Exposure: People living near facilities that release benzene and other hazardous chemicals into the environment may also face increased risks.

Myelodysplastic Syndromes (MDS):

• MDS Overview: Myelodysplastic Syndromes are a group of clonal hematopoietic stem cell disorders characterized by abnormalities in blood cell production. These abnormalities include ineffective hematopoiesis, cytopenias (low blood cell counts), and chromosomal abnormalities.

• Progression to AML: Some individuals with MDS may experience a transformation of their condition to AML, including sAML. This progression occurs when MDS's genetic mutations and cellular dysregulation evolve into full-blown leukemia.

Risk Groups:

• MDS Patients: Individuals already diagnosed with MDS are at a significantly higher risk of developing sAML than the general population.

• Specific Genetic Mutations: Certain genetic mutations, such as mutations in TP53 or complex cytogenetics in MDS, are associated with an increased risk of progression to sAML.

How Is the Diagnosis of Secondary Acute Myeloid Leukemia Done?

The diagnosis can be performed in the following ways:

Clinical Evaluation:

• Detailed Medical History: Healthcare professionals start by taking a thorough medical history from the patient. This includes information about prior cancer treatments, exposure to toxins, and known hematological conditions.

• Symptom Assessment: Clinicians assess the patient's symptoms, which can vary but often include fatigue, recurrent infections, easy bruising, and bleeding. These symptoms can be indicative of hematological disorders like sAML.

Complete Blood Count (CBC):

• Initial Blood Test: A Complete Blood Count (CBC) is one of the initial diagnostic tests performed. This blood test measures the number and characteristics of different blood cell types, including red blood cells (RBCs), white blood cells (WBCs), and platelets.

• Abnormalities: sAML often presents with abnormalities in these blood cell counts. Common findings include:

• Anemia: A decreased number of red blood cells, leading to fatigue and weakness.

• Thrombocytopenia: A reduced number of platelets, which can result in easy bruising and bleeding.

• Leukopenia: A decreased number of white blood cells can impair the body's ability to fight infections.

Bone Marrow Aspiration and Biopsy:

• Definitive Diagnosis: The cornerstone of diagnosing sAML is a bone marrow aspiration and biopsy. This procedure involves the removal of a small sample of bone marrow from the hipbone (usually the posterior iliac crest).

• Examination of Blast Cells: The collected bone marrow sample is examined under a microscope to identify and quantify blast cells. In sAML, these immature myeloid cells often accumulate in the bone marrow.

• Cell Morphology: The appearance and morphology of these blast cells can provide important information about the subtype of AML.

Cytogenetic and Molecular Testing:

• Molecular Analysis: After the initial diagnosis of sAML, further testing is essential to determine the genetic and molecular characteristics of the leukemia. This is crucial for risk stratification and guiding treatment decisions.

• Genetic Abnormalities: Testing may include identifying specific genetic mutations or chromosomal abnormalities associated with sAML. Common mutations examined include FLT3, NPM1, and IDH1/2 mutations.

• Risk Stratification: The presence or absence of certain genetic mutations can help stratify patients into different risk groups, which can inform treatment decisions.

Additional Tests:

• Flow Cytometry: Flow cytometry is often used to analyze the immunophenotype of leukemic cells, helping to further classify the AML subtype.

• Lumbar Puncture: In some cases, a lumbar puncture (spinal tap) may be performed to assess if leukemia has spread to the cerebrospinal fluid.

How Is the Treatment of Secondary Acute Myeloid Leukemia Done?

The following steps can be taken for the treatment of sAML:

Chemotherapy:

• Induction Chemotherapy: This is typically the initial treatment approach for sAML. It involves using powerful chemotherapy drugs to eradicate leukemia cells in the bone marrow and peripheral blood. Common drugs used in induction therapy for AML include cytarabine and anthracyclines like daunorubicin or idarubicin.

• Combination Chemotherapy: These drugs are often combined to maximize their effectiveness. The goal of induction chemotherapy is to achieve remission by reducing the number of leukemia cells to an undetectable level in the bone marrow.

Stem Cell Transplantation:

• Allogeneic Stem Cell Transplantation: This treatment offers a potential cure for sAML. It involves replacing the patient's bone marrow, which contains leukemia cells, with healthy donor cells. These donor cells can help reestablish normal blood cell production.

• Conditioning Regimen: Patients typically undergo a conditioning regimen that includes high-dose chemotherapy or total body irradiation before the transplant. This regimen destroys any remaining leukemia cells and prepares the bone marrow for the transplant.

• Matching Donors: Finding a suitable donor with compatible human leukocyte antigen (HLA) markers is crucial for a successful transplant.

Targeted Therapies:

• FLT3 Inhibitors: In recent years, targeted therapies have emerged as promising options for specific genetic subtypes of sAML. FLT3 inhibitors, such as Midostaurin or Gilteritinib, treat sAML cases with FLT3 mutations. These drugs specifically target the mutated FLT3 protein, inhibiting its activity and slowing the progression of the disease.

• IDH Inhibitors: IDH inhibitors, such as Ivosidenib or Enasidenib, are used for sAML cases with IDH1 or IDH2 mutations. These inhibitors block these mutated enzymes' abnormal activity, helping restore normal cell differentiation.

Supportive Care:

• Symptom Management: Patients with sAML often experience symptoms such as fatigue, anemia, and susceptibility to infections. Supportive care measures are essential to manage these symptoms and improve the patient's quality of life.

• Blood Transfusions: Patients may require regular blood transfusions to address anemia or thrombocytopenia.

• Infection Prevention: Due to weakened immune function from chemotherapy and leukemia, infection prevention measures, such as antibiotics and antifungal medications, may be necessary.

• Monitoring and Complication Management: Frequent monitoring for potential complications, such as febrile neutropenia (a condition characterized by fever and low neutrophil counts), is vital. Prompt management of these complications is essential to ensure patient safety.

Conclusion

Secondary Acute Myeloid Leukemia is a complex and challenging condition that often arises as a consequence of prior medical treatments or exposures. Early diagnosis and appropriate treatment are critical for improving patient outcomes.