Acute Myeloid Leukemia: From Diagnosis to Treatment

Dear Colleagues,

Acute myeloid leukemia (AML) is an aggressive hematologic malignancy and the most common acute leukemia in adults.  For many years, the standard treatment for AML consisted of intensive and prolonged chemotherapy with a combination of cytarabine and an anthracycline, commonly referred to as “7+3”. In addition to the toxicities and lengthy, frequent hospitalizations associated with this regimen, most patients, including those with "favorable" risk factors experienced frequent relapses and short survival times. Over the past two decades, the genetic and molecular underpinnings of AML have become better defined, thereby paving the way for refinements in the disease classification, risk-stratification, and development of newer and better tolerated treatment options. As such, the diagnosis and treatment paradigm for AML has become more personalized, but also more complex.  In this Special Issue, we focus on the most recent updates regarding AML diagnosis and classification, as well as on newest therapies for AML that are currently available and those under development. We will discuss factors that are considered when tailoring a treatment decision, both in newly diagnosed and relapsed/refractory settings, including the role of allogeneic stem cell transplant and the current state of cellular therapies.

In this Special Issue, original research articles and reviews within the scope of the topics described above are welcome.

I look forward to receiving your contributions.

Dr. Bhavana Bhatnagar
Guest Editor

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• acute myeloid leukemia
• treatment
• risk factors
• classification
• diagnosis

Title: Preliminary clinical activity of the Axl inhibitor TP-0903 in relapsed or refractory acute myeloid leukemia with FLT3-ITD
Authors: Bhavana Bhatnagar 1, Uma Borate 2, Kaitlyn Dvorak 2, Daelynn Buelow 2, James S. Blachly 2),
Affiliation: 1 West Virginia University 2 Ohio State University
Abstract: Acute myeloid leukemia (AML) is the most common acute leukemia in adults and is characterized by the acquisition of sequential genetic and molecular aberrations that culminate in the expansion of myeloid blasts in the blood and marrow leading to severely impaired hematopoiesis. Among the most common of these mutations are those in the fms-like tyrosine kinase 3 (FLT3) gene, which are observed in approximately 30-35% of AML patients (ref) and primarily include internal tandem duplications (ITDs) in 25% and tyrosine kinase domain (TKD) point mutations in 5% (Pemmaraju Cancer 2011, Reindl Blood 2006 and Thiede Blood 2002), resulting in constitutive activation of FLT3 signaling. AML with FLT3-ITD has been well described as an especially poor biological subtype, as patients often present with proliferative disease and display a short disease-free interval following standard AML-directed chemotherapy (Adolfsson, Breccia and Whitman Cancer Res 2001). As such, molecularly targeted therapies directed at inhibiting FLT3 signaling have been an attractive treatment option. Currently, there are two FLT3 inhibitors that are approved by the United Stated Food and Drug Administration. One explanation for the lack of durable responses is acquired resistance to FLT3 inhibition as a result of increased phosphorylation of Axl, another receptor tyrosine kinase, which has been shown, in preclinical studies, to have increased levels of phosphorylation in FLT3 resistant cell lines (Park et al, Leukemia 2015, PMID: 26172401). Therefore, inhibition of Axl is an important pathway by which to affect FLT3 inhibition. TP-0903 is a multikinase inhibitor, which in preclinical studies has been shown to overcome drug resistance in AML cell lines (Jeon et al JCI Insight). We, therefore, sought to evaluate the clinical activity of this drug in a pilot phase 1 study of patients with relapsed or refractory AML and FLT3-ITD mutations.