Decoding the Inflammasome Influence on Treatment Response in Acute Myeloid Leukemia

Acute myeloid leukemia (AML) is a highly aggressive and unfavorable malignancy primarily affecting bone marrow (BM) myeloid cells, particularly in older individuals. The standard treatment for fit, intermediate and high-risk patients involves chemotherapy followed by allogeneic hematopoietic stem cell transplantation (HSCT). However, around 60% of patients experience relapse, requiring second-line therapies that offer a reduced likelihood of achieving a permanent cure.

Inflammation significantly influences AML development, progression, leukemic cell behavior, and treatment response. Interactions between leukemic cells and microenvironment promote their growth, survival, and drug resistance. The inflammasome, an intracellular complex crucial for promoting inflammation, triggers the release of the proinflammatory cytokines interleukin (IL)-1beta and IL-18, and induces pyroptosis (inflammatory cell death) in response to inflammatory stimuli. There is growing evidence suggesting a link between the inflammasome and AML, with components of the inflammasome being overexpressed in leukemic cells. The precise mechanisms by which the inflammasome and its activation pathways influence AML still need to be fully understood.

We speculate that excessive inflammasome activity in AML disrupts the balance of cytokine production, leading to chronic inflammation, which interferes with the normal development and function of hematopoietic cells in the BM microenvironment. This heightened inflammasome signature could impact the way patients respond to chemotherapy, potentially altering inflammatory processes, ultimately reducing the efficacy of the treatment. Variations in inflammasome activation among AML patients may explain differences in treatment outcomes, including response rates, hematopoietic recovery, remission duration, and overall survival.

Understanding the molecular mechanisms involved in AML, particularly the role of the inflammasome, could allow a better disease risk stratification and the development of potential targeted therapies and interventions, which could improve treatment outcomes. More specifically, identifying potential therapeutic targets within the inflammasome pathway, may drive to the design of new treatment strategies, precisely aimed at correcting inflammasome dysregulation in AML. From the clinical point of view, these insights could assist healthcare professionals in taking informed decisions in the management of AML patients. By modulating inflammasome activity or targeting specific pathway components, we could develop personalized treatment approaches tailored to individual patient needs, optimizing treatment response and possibly minimizing chemotherapy-related side effects. This personalized approach has the potential to enhance the quality of life for patients, reduce complications, and increase the overall effectiveness of treatments.

During the Study period patients referring to the clinical centers will undergo the standard diagnostic and therapeutic process for their pathology, according to international guidelines. For all the patients that will agree to participate, clinical data and biological samples will be analyzed for the aims of the Study. The retrospective part of the data and material collection must have bio-banked material in compliance with the ethics and regulatory standards for the research purpose.