Comprehensive deciphering of the genetic, epigenetic and immunogenetic mechanisms of post-allogeneic transplant relapse in acute myeloid leukemia

Uncovering the secrets of post-transplant relapse in acute myeloid leukemia

An early-career clinician-investigator in Toronto is hoping to find new ways to personalize treatments for patients with acute myeloid leukemia (AML) thanks to new funding from the Marathon of Hope Cancer Centres Network (MOHCCN).

Dr. Igor Novitzky-Basso, a hematologist at the Princess Margaret Cancer Centre, will use funds from his new Clinician-Scientist Award to advance research that will help predict which patients with AML will relapse after receiving a stem cell transplant and find ways to treat those patients with personalized treatments before relapse occurs.

“AML is an aggressive form of blood cancer that often requires a hematopoietic cell transplant (HCT) from a donor as the only potentially curative treatment. However, despite the success of HCT in many cases, some patients still experience a relapse, where the leukemia returns after the transplant,” explains Dr. Novitzky-Basso.

The reasons behind these relapses are not fully understood, posing a significant challenge in the treatment of AML. Dr. Novitzky-Basso’s project seeks to address this critical gap in knowledge by leveraging advanced genomic technologies to explore the underlying causes of post-transplant relapse.

“This project will focus on two key areas: the genetic mutations that drive leukemia recurrence and the mechanisms by which tumour cells evade the new donor immune system after HCT,” he says. “This funding will allow us to explore innovative genomic and immunogenetic approaches, aiming to uncover mechanisms of relapse and ultimately improve patient outcomes."

The research will build on previous work where Dr. Novitzky-Basso’s team used next-generation sequencing to identify and monitor subgroups of leukemic cells, known as clones, in patients after HCT. Their findings showed that sequencing was effective in predicting AML relapse, but it could not provide a complete picture of the mutational landscape that led to that relapse.

To fill this gap, the team will employ a more comprehensive approach that incorporates whole genome sequencing (WGS), a cutting-edge technology that can map out the entire mutational landscape of relapsed AML. By analyzing both the DNA and RNA of single cells from patients at the time of diagnosis and at relapse, the researchers will dissect the changes in gene expression, particularly in immune regulatory genes, that may allow tumour cells to escape immune surveillance. Additionally, the project will utilize whole transcriptomic sequencing and single-cell transcriptomics to further refine their understanding of the clonal architecture of relapsed leukemic cells.

By combining these genomic technologies, Dr. Novitzky-Basso and his team hope to identify new biomarkers and therapeutic targets that could lead to more effective strategies for preventing relapse in AML patients post-HCT. The ability to predict and prevent relapse could significantly improve survival rates and quality of life for patients battling this aggressive form of leukemia. 

"This recognition is a tremendous honour that will significantly impact our research and patients," says Dr. Novitzky-Basso about his Clinician-Scientist Award.  

The $225,000 award is for three years and will be matched by the University Health Network to total $450,000.