Therapy of Acute Myeloid Leukemia

Update on Non-M3 Acute Myeloid Leukemia — Etiology, Classification, Risk Stratification, Emergencies, Complications, Disease in Special Circumstances and Current and Future Therapeutics

“…The accumulation of genetic mutations and cytogenetic abnormalities, within partially differentiated cells belonging to the myeloid lineage, following the exposure to benzene and cytotoxic anticancer agents can give rise to malignancies such as AML [4]. However, the etiology of AML is multifactorial and the following can predispose to the development of AML: (1) exposure to ionizing radiation and chemicals, (2) long-term exposure to benzene, (3) exposure to cytotoxic chemotherapy in t-AML, (4) infection with retroviruses, (5) familial forms of AML, (6) secondary to myelodysplastic syndrome (MDS), (7) secondary to congenital disorders of DNA repair such as Fanconi anemia, and (8) secondary to chronic myeloproliferative neoplasms (MPNs) such as: polycythemia rubra vera, chronic myeloid leukemia (CML), essential thrombocythemia and primary myelofibrosis [2,4,5]. Thus, AML is a heterogeneous disease in terms of the underlying chromosomal or molecular aberrations [13].…”

“…The available therapeutic options for older patients with AML include: (1) standard induction therapy with 7+3 regimen, (2) hypomethylating agents such as azacitidine and decitabine, (3) nucleoside analogs such as clofarabine and sapacitabine, (4) immunomodulatory agents such as lenalidomide, (5) farnesyl transferase inhibitors such as tipifarnib, (6) monoclonal antibodies such as gemtuzumab ozogamicin (GO, myelotarg), (7) low-dose cytarabine, and (8) the best supportive care with blood product transfusions, antimicrobials as needed and oral cytotoxic drugs such as hydroxyurea [10,11,57,58].…”

“…(1) replacement of daunorubicin by idarubicin, (2) replacement of daunorubicin by mitoxantrone, (3) escalation of daunorubicin dose, (4) addition of etoposide to the 7+3 regimen, (5) addition of thioguanine to the 7+3 regimen, (6) replacement of daunorubicin by amsacrine and gemtuzumab ozogamicin, (7) the use of HiDAC alone or in combination with fludarabine and/ or G-CSF as induction therapy, and (8) incorporation of new agents such as cladarabine, clofarabine, lomustine, AC-220 and sorafenib [96,97,100].…”

“…Leukemic stem cells (LSCs) play a major role in the maintenance of AML, while the bone marrow (BM) microenvironment permits leukemogenesis as well as disease progression [2,3]. Various environmental exposures such as exposure to chemicals and radiation, and various infections in addition to hereditary factors can predispose vulnerable individuals to develop AML [2,4,5]. The two-hit hypothesis of leukemogenesis is characterized by two types of genetic mutations that evolve following certain environmental exposures [2].…”