Novel Therapies in AML: Reason for Hope or Just Hype?

Abstract

We have entered the genomic sequencing era in the treatment of acute myeloid leukemia (AML); our patients increasingly and justifiably demand personalized treatment based on aberrations of their own leukemia. Except in rare cases we are not yet able to provide truly personalized therapy, so the question of "hope or hype?" posed by the American Society for Clinical Oncology (ASCO) for this educational topic is quite timely. The answer based solely on advances in genomic sequencing is "both". There is an element of expectation among the public that we are "almost there" in solving the genetic cancer puzzle, an expectation indeed based on hype. However, there is no question that ultimate success lies in understanding the genetic underpinnings of disease. When decades of research in molecular biology and immunology are combined with transformative advances in cancer genetics, the answer is undeniably that our patients finally have reason for hope. Here, we review selected novel therapies for AML in areas such as immunotherapeutics, epigenetics, kinase inhibition/pathway inhibition, and the marrow microenvironment.

Expression Levels of Human Equilibrative Nucleoside Transporter 1 and Deoxycytidine Kinase Enzyme as Prognostic Factors in Patients with Acute Myeloid Leukemia Treated with Cytarabine

“…Clofarabine primarily requires hENT2 , and only a minor proportion of hENT1 , to be transported into the cell, and it also requires phosphorylation by dCK and deoxyguanosine kinase. The sensitivity of Ara-C-resistant leukemia to clofarabine may be related to the affinity of this drug for other transporters and activation by other kinases [26,27,28]. …”

Effective Dendritic Cell-based Immunotherapeutic Vaccines for Acute Myeloid Leukemia (AML)

“…Moreover, the possibility of producing fusion DCs and AML blast and the in vivo activity of fusion cells have been shown in a phase I clinical trial. The authors could find the expansion of bone marrow infiltrating AML reactive T cells in the patients [78]. In another study, a 23-month remaining in remission was reported in 9 of 13 evaluable AML patients who had received vaccination with DC/leukemia fusion cells after remission [79].…”

“…Hopeful investigations are ongoing to use the TLR-DCs in combination with the other modalities like blocking of checkpoint molecules (e.g. CTLA4) or dampening the immunosuppressive factors [78]. There are different results on overall survival rates of AML patients in various clinical trials; however, the best results are related to studies which have considered all important aspects of designing a vaccination protocol.…”

“…There are different results on overall survival rates of AML patients in various clinical trials; however, the best results are related to studies which have considered all important aspects of designing a vaccination protocol. These factors include the process of generating mature leukemic or monocyte derived antigen specific-DCs, overcoming the immunosuppressive milieu, timing of injection, route and dose of vaccination, overall tumor burden as well as knowing the characteristics of LSCs to target them [78]. Although the exact immunophenotype of the LSCs is still unclear, CD123 (IL-3R) is constitutively expressed on both LSCs and leukemic cells and is a promising therapeutic target for AML.…”

Correlation between p65 and TNF-α in patients with acute myelocytic leukemia

“…It is the most common form of adult leukemia and the survival rate is very low (1)(2)(3). Epidemiological studies from the United States National Cancer Institute reported that the overall incidence rate of AML in the USA between 2001 and 2005 was 3.6/100,000 individuals, and the mortality rate was 2.8/100,000 individuals (4).…”