Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a heterogenous disease with multifactorial pathology including, but not limited to, genetics, cell lineage – erythroid, megakaryocytic, and monocytic – and degree of maturation of blast cells. The World Health Organization has classified this condition into four major types and many subtypes according to these characteristics, with the aim of projecting prognosis and guiding therapy. The age standardized incidence rate of AML is 1.54 per 100,000 and its prevalence ranges between 0.6 - 11.0 per 100,000, for all age categories, genders, and ethnicities.1, 2 Despite advances in diagnostic and therapeutic medicine, AML remains a devastating disease, with only a 15-30% overall survival rate. However, newer treatments – such as allogeneic stem cell transplant and immunotherapy – offer hope for an improved outlook.

Formation

AML manifests itself when the hematopoietic progenitor cells in bone marrow –myeloblasts – fail to differentiate into predefined healthy cells, causing accumulation of myeloid precursors in the marrow. This disruption in the production of normal cells leads to a generalized pancytopenia, resulting in dramatically sudden and severe clinical onset in the form of opportunistic infections and bleeding.3

The mechanism behind AML is attributable to changes in the genetic code of blood stem cells; several mutations are linked to causing and promoting the disease, including FLT3, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, p53, NRAS, CEBPA, WT1.4

Diagnosis and treatment assessment

The diagnosis and risk stratification of AML is based on morphology Fig.1, histochemistry, immunophenotyping, and DNA sequencing performed on bone marrow tissue. Newly diagnosed AML is defined as a myeloid blast count of > 20%, and the presence of myeloperoxidase positive Auer rods on cytoplasmic staining, along with genetic alterations on karyotyping. The treatment is primarily chemotherapy given in induction and consolidation phases based on patient-specific factors and the type of disease.5

Acute Myeloid Leukemia

Figure 1. Example micrograph of an acute myeloid leukemia.9

Relapse rates are very high, and the condition is rarely curable, therefore monitoring of minimal residual disease via cell counts and cytogenetics is crucial.4 The major cause of the cancer coming back is drug resistance mainly mediated by leukemic stem cells (LSCs), which renew in an unlimited manner and produce more blasts, worsening the disease.6

Cell markers

Myeloblasts express antigenic factors which are also found on healthy immature myeloid cells, including CD13, CD33, and CD34. The morphological subtype of AML and the lineage progenitor involved denote whether the cell markers are monocytic (CD4, CD14, CD11b), erythroid (CD36, CD71), and megakaryocytic (CD41a, CD61).7 Quantitative RT-PCR can be used to identify markers for LSCs – CD34, CLL-1, TIM-3, and BMI-1 – in patients with relapse.6

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References

  1. Dong, Y., Shi, O et al. (2020) Leukemia incidence trends at the global, regional, and national level between 1990 and 2017. Exp Hematol Oncol 9(14). https://doi.org/10.1186/s40164-020-00170-6
  2. Deborah P Lubeck, Mark Danese et al. (2016) Systematic Literature Review of the Global Incidence and Prevalence of Myelodysplastic Syndrome and Acute Myeloid Leukemia. Blood 128 (22): 5930. doi: https://doi.org/10.1182/blood.V128.22.5930.5930
  3. Vinay Kumar, Abul K. Abbas, Jon C. Aster. (2021). Robbins Basic Pathology. 9th edition. Elsevier Saunders. 444-445.
  4. Kantarjian, H., Kadia, T et al. (2021). Acute myeloid leukemia: current progress and future directions. Blood Cancer J. 11(41). https://doi.org/10.1038/s41408-021-00425-3
  5. Schiffer CA, Stone RM. Morphologic Classification and Clinical and Laboratory Correlates. In: Kufe DW, Pollock RE, Weichselbaum RR. (2003). Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker. Available from: https://www.ncbi.nlm.nih.gov/books/NBK13452/
  6. Saultz, J. N., & Garzon, R. (2016). Acute Myeloid Leukemia: A Concise Review. Journal of clinical medicine. 5(3), 33. https://doi.org/10.3390/jcm5030033
  7. Darwish, N. H., Sudha, T et al. (2016). Acute myeloid leukemia stem cell markers in prognosis and targeted therapy: potential impact of BMI-1, TIM-3 and CLL-1. Oncotarget. 7(36): 57811–57820. https://doi.org/10.18632/oncotarget.11063
  8. Ding, Y., Gao, H et al. (2017). The biomarkers of leukemia stem cells in acute myeloid leukemia. Stem cell investigation. 41(9). https://doi.org/10.21037/sci.2017.02.10
  9. Based on https://media.istockphoto.com/photos/micrograph-of-acute-myeloid-leukemia-picture-id614122970?s=612x612

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