Acute Myeloid Leukemia (AML) is a cancer of the blood and bone marrow, characterized by the rapid, uncontrolled growth of abnormal white blood cells called myeloblasts. This proliferation interferes with the production of healthy blood cells, leading to anemia, infection, and bleeding. AML is categorized by how it develops: primary AML appears spontaneously (de novo), while secondary AML (sAML) develops following a pre-existing medical condition or prior treatment. Secondary AML is the focus of this analysis.
Defining Secondary Acute Myeloid Leukemia
Secondary Acute Myeloid Leukemia (sAML) is diagnosed when the cancer arises in a patient with a prior hematologic disorder or following exposure to cancer therapies. It accounts for approximately 20% to 30% of all AML cases. The diagnosis of sAML requires identifying one of two specific antecedent scenarios.
The first category is Acute Myeloid Leukemia with Myelodysplasia-Related Changes (AML-MRC), which evolves from an earlier, non-leukemic blood condition. The second is Therapy-Related AML (t-AML), caused by previous exposure to chemotherapy or radiation used to treat an unrelated cancer. This classification is important because the underlying biological changes in sAML affect how the disease responds to standard treatments.
Primary Pathways Leading to Secondary AML
The development of sAML is linked to two distinct forms of genetic damage: previous cancer treatment or the progression of an unstable blood disorder. Therapy-Related AML (t-AML) occurs when cytotoxic agents used to treat a primary malignancy, such as breast cancer or lymphoma, cause damage to the DNA of bone marrow stem cells. This exposure creates an environment conducive to leukemic transformation.
Alkylating drugs and radiation therapy often lead to characteristic chromosomal losses, particularly affecting chromosomes 5 and 7, and the development of complex karyotypes. This form of t-AML typically has a longer latency period, developing five to seven years after the initial treatment. Topoisomerase II inhibitors cause different genetic damage, resulting in specific chromosomal translocations, most commonly involving the KMT2A gene on chromosome 11. This subtype generally develops more quickly, with onset occurring within one to three years after exposure.
The second pathway involves the transformation of a pre-existing blood condition, primarily Myelodysplastic Syndromes (MDS) or Myeloproliferative Neoplasms (MPN). MDS is a disorder where the bone marrow produces dysfunctional and immature blood cells. Over time, early mutations in genes like TET2 or U2AF1 accumulate additional genetic changes, pushing the unstable blood cell population toward AML. This progression creates the subtype classified as AML-MRC.
Key Biological Differences from Primary AML
Secondary AML is biologically distinct from primary AML, a difference that dictates its aggressive nature. While primary AML often features specific, favorable genetic changes, sAML is characterized by complex and unfavorable chromosomal abnormalities. These often include the loss of entire chromosomes, resulting in a complex karyotype strongly associated with poor outcomes.
sAML cells frequently harbor specific gene mutations that are rare in primary AML. Mutations in genes involved in RNA splicing and epigenetic regulation, such as SRSF2, ASXL1, EZH2, and TP53, are specific to secondary forms. The presence of these “secondary-type” mutations indicates a history of clonal evolution and confers a worse prognosis, even in cases that technically meet the criteria for primary AML.
The leukemic stem cells that fuel sAML often originate from a more primitive, earlier stage of blood cell development compared to those in primary AML. This difference contributes to the cancer’s resistance to standard chemotherapy regimens. Consequently, patients with sAML achieve lower rates of complete remission when treated with conventional intensive chemotherapy.
Treatment Considerations and Prognosis
The distinct biology of sAML necessitates a modified and often more aggressive treatment strategy than that used for primary AML. Standard intensive induction chemotherapy is less effective, yielding lower remission rates and shorter survival. This reduced efficacy is attributed to the unfavorable genetic profile and the patient’s typically older age and prior medical history.
A targeted liposomal formulation of chemotherapy, CPX-351, was developed for fit patients with newly diagnosed t-AML or AML-MRC, demonstrating improved overall survival compared to traditional induction therapy. For patients who cannot tolerate intensive chemotherapy, combinations of hypomethylating agents with newer drugs like Venetoclax have become an important, less intense option.
For patients who are physically able, Allogeneic Hematopoietic Stem Cell Transplantation (HSCT), or a bone marrow transplant, remains the only cure for sAML. This procedure replaces the patient’s cancerous bone marrow with healthy donor stem cells, offering the best chance for long-term survival. Despite therapeutic advancements, the prognosis for sAML remains guarded, with the five-year survival rate generally reported to be under 30%.