Targeted Therapeutic Approach Based on Understanding of Aberrant Molecular Pathways Leading to Leukemic Proliferation in Patients with Acute Myeloid Leukemia

Abstract

Acute myeloid leukemia (AML) is a heterogenous hematopoietic neoplasm with various genetic abnormalities in myeloid stem cells leading to differentiation arrest and accumulation of leukemic cells in bone marrow (BM). The multiple genetic alterations identified in leukemic cells at diagnosis are the mainstay of World Health Organization classification for AML and have important prognostic implications. Recently, understanding of heterogeneous and complicated molecular abnormalities of the disease could lead to the development of novel targeted therapeutic agents. In the past years, gemtuzumab ozogamicin, BCL-2 inhibitors (venetovlax), IDH 1/2 inhibitors (ivosidenib and enasidenib) FLT3 inhibitors (midostaurin, gilteritinib, and enasidenib), and hedgehog signaling pathway inhibitors (gladegib) have received US Food and Drug Administration (FDA) approval for the treatment of AML. Especially, AML patients with elderly age and/or significant comorbidities are not currently suitable for intensive chemotherapy. Thus, novel therapeutic planning including the abovementioned target therapies could lead to improve clinical outcomes in the patients. In the review, we will present various important and frequent molecular abnormalities of AML and introduce the targeted agents of AML that received FDA approval based on the previous studies.

A Clinical Phase 1B Study of the CD3xCD123 Bispecific Antibody APVO436 in Patients with Relapsed/Refractory Acute Myeloid Leukemia or Myelodysplastic Syndrome

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have…”

“…The greatest challenge in the field of AML therapy is achieving deep CRs and longterm leukemia-free survival in R/R AML patients [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite the fact that we have gained new insights and a better understanding of cell-intrinsic drivers of AML and new drugs have been developed for targeting select somatic mutations, the majority of R/R AML patients die of leukemia [8][9][10][11][12][13][14][15][16].…”

“…The rate of new cases of AML is 4.3 per 100,000 men and women per year, and the death rate is 2.8 per 100,000 men and women per year. Several targeted medicines, such as FLT3 inhibitors, IDH1/2 inhibitors, and BCL-2 inhibitor Venetoclax, as well as biotherapeutics (e.g., antibody-drug conjugates) for AML therapy have been developed and approved by the FDA over the last 10 years [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. Despite these recent advances in therapy, more than 50% of patients who achieve a remission eventually relapse, and the five-year overall survival remains at 29.5%.…”

Molecular Mechanism Investigation on Monomer Kaempferol of the Traditional Medicine Dingqing Tablet in Promoting Apoptosis of Acute Myeloid Leukemia HL-60 Cells

“…However, approximately 65% of patients remain to undergo relapse within 3 to 5 years [ 37 ]. The overall survival rate of adults is only 24% to 28% [ 38 ].…”

Kinesin family member 2A acts as a potential prognostic marker and treatment target via interaction with PI3K/AKT and RhoA/ROCK pathways in acute myeloid leukemia

“…Although novel therapies have been introduced for AML treatment over past decades, limited progress has been made in enhancing patient survival profile ( 5 , 6 ). Hence, to develop novel treatment options for AML, its associated molecule mechanisms, such as driver genes and pathways, have been extensively studied ( 7 , 8 ).…”