Frontline treatment of acute myeloid leukemia in adults

Abstract

Recent years have highlighted significant progress in understanding the underlying genetic and epigenetic signatures of acute myeloid leukemia(AML). Most importantly, novel chemotherapy and targeted strategies have led to improved outcomes in selected genetic subsets. AML is a remarkably heterogeneous disease, and individualized therapies for disease-specific characteristics (considering patients' age, cytogenetics, and mutations) could yield better outcomes. Compared with the historical 5-to 10-year survival rate of 10%, the survival of patients who undergo modern treatment approaches reaches up to 40-50%, and for specific subsets, the improvements are even more dramatic; for example, in acute promyelocytic leukemia, the use of all-trans retinoic acid and arsenic trioxide improved survival from 30 to 40% up to 80 to 90%. Similar progress has been documented in core-binding-factor-AML, with an increase in survival from 30% to 80% upon the use of high-dose cytarabine/fludarabine/granulocyte colony-stimulating factor combination regimens. AML treatment was also recently influenced by the discovery of the superiority of regimens with higher dose Ara-C and nucleoside analogues compared with the "7+3"regimen, with about a 20% improvement in overall survival. Despite these significant differences, most centers continue to use the "7+3" regimen, and greater awareness will improve the outcome. The discovery of targetable molecular abnormalities and recent studies of targeted therapies (gemtuzumab ozagomycin, FLT3 inhibitors, isocitrate dehydrogenase inhibitors, and epigenetic therapies), future use of checkpoint inhibitors and other immune therapies such as chimeric antigen receptor T-cells, and maintenance strategies based on the minimal residual disease evaluation represent novel, exciting clinical leads aimed to improve AML outcomes in the near future.

Keywords: Acute myeloid leukemia; Frontline treatment; High dose Ara-C; Nucleoside analogues.

Figure 1

Predisposing factors of AML

Figure 2. Overall survival of patients classified by the ELN and MRC classification systems

Overall survival of patients <60 years (N=487) classified by the ELN (A) and MRC (B) classification systems. Overall survival of patients ≥60 years (N=539) classified by the ELN (C) and MRC (D) classification systems. FAV, favorable; INT, intermediate; ADV, adverse (adopted from Kadia T, et al. Br J Haematol 2015 Feb 25)

Figure 3. Potential targets and targeted therapies in adults AML

Abbreviations: GO, gemtuzumab ozagomicin; PD1, programmed cell death 1; PDL-1, programmed death-ligand 1; LAG-3, lymphocyte-activation gene 3; IDH (1,2), isocitrate dehydrogenase; MDM2, mouse double minute 2 homolog; MLL, mixed lineage leukemia; CXCR4, C-X-C chemokine receptor type 4; DOT1L, DOT1-like histone H3 methyltransferase; BET, Bromodomain and extraterminal domain family; PI3K, phosphoinositide 3-kinase; MEK, mitogen/extracellular signal-regulated kinase; TET2, Tet methylcytosine dioxygenase 2; FLT3, fms-related tyrosine kinase 3; DNMT3A, DNA (cytosine-5-)-methyltransferase 3 alpha