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Diagnosis and Discussion: Case 1142

Discussion

Acute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by the clonal expansion of immature myeloid cells. It often arises de novo but can also evolve from pre-existing myelodysplastic syndromes (MDS) or other myeloid neoplasms, such as myeloproliferative neoplasms (MPNs) and MDS/MPNs like chronic myelomonocytic leukemia (CMML). In this case, the features that raise the possibility that the AML arose from myeloid neoplasm like MDS are increased dysplastic megakaryocytes, fibrosis, and genetic abnormalities of chromosome 5q and 20q deletions and complex karyotype.

MDS is a heterogeneous group of clonal hematopoietic disorders characterized by ineffective hematopoiesis, cytopenia(s), usually hypercellular marrow, and dysplastic changes in one or more cell lines. Over time, MDS may transform into AML, which is referred to as secondary AML. The transformation often involves the acquisition of additional genetic mutations that drive leukemogenesis. The risk of progression is higher in cases with poor prognostic factors, such as complex karyotype, high-risk mutations (e.g., TP53, ASXL1), or the presence of therapy-related MDS.

MPNs, including polycythemia vera, essential thrombocythemia, and primary myelofibrosis, are characterized by the clonal proliferation of one or more myeloid lineages. These disorders can evolve into AML, particularly in primary myelofibrosis (PMF), where the progression to secondary AML is a well-known complication. The evolution from MPNs to AML is often driven by the accumulation of secondary mutations and may involve the acquisition of mutations in genes like TET2, ASXL1, and JAK2.

CMML is a type of leukemia that shares features of both MPNs and MDS. It is characterized by monocytosis, cytopenia(s), and dysplastic features. Some patients with CMML may eventually develop monocytic AML, particularly those with more severe dysplastic features or higher mutation burdens. The progression from CMML to AML is less frequent compared to MDS, but it represents an important clinical entity due to the poorer prognosis and therapeutic challenges it presents.

Secondary AML tends to have a poorer prognosis compared to de novo AML. The presence of a pre-existing myelodysplastic or myeloproliferative condition often means that the leukemic clone has already undergone significant genetic and epigenetic changes, making it less responsive to therapy. The risk of transformation is influenced by the underlying myeloid disorder, the presence of specific mutations, and the patient's age and overall health.

The transformation from myeloid neoplasms like MDS, CMML, and MPNs to secondary AML represents a complex process driven by genetic and epigenetic alterations. This progression has significant clinical implications, as secondary AML tends to have a more aggressive course, poorer prognosis, and reduced response to conventional therapies.

Of note, a monoallelic TP53 mutation has been shown to have a worse prognosis in AML, and because of this, the International Consensus Classification (ICC) established the entity, AML with mutated TP53. The WHO 5th edition classification does not recognize this entity and would instead classify this case as AML, myelodysplasia-related because of the complex karyotype and 5q deletion. In MDS, bi-allelic TP53 mutations or TP53 mutation with loss of heterozygosity are associated with increased risk of progression to AML. However, the implications of a mono-allelic TP53 mutation in a low-grade myeloid neoplasm is less clear but may not have the same increased risk.

References

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