Understanding combination cytotoxic chemotherapy in Acute Myeloid Leukaemia

Acute Myeloid Leukaemia (AML) is the most common, aggressive human leukemia. Within the whole group of AML patients there is a subset of patients, typically younger (less than 65 years of age) who receive intensive conventional combination cytotoxic chemotherapy (anthracyclines and nucleoside analogues), who have a higher cure rate (~65%). Despite these cytotoxic drugs being in routine clinical use since the 1970’s, the field surprisingly still does not understand why these patients are cured. Conventional wisdom is that these patients are cured, because intensive combination cytotoxic chemotherapy kills all AML cells. However, this has never been rigorously proven and alternative hypotheses have not been tested.

This proposal will test if in patients who are cured, compared to those who are not, if eradication of all AML cells, could result from:
1. Increased killing of AML from cytotoxic chemotherapy.
2. An autologous innate and, or, acquired immune anti-AML cell response.
3. A combination of (1) and (2).

Specific Aims:

Using patient samples from cured patients and patients who relapse we will:
1. Contrast amount of AML cells left after treatment (measurable residual disease, MRD), in bone marrow (BM) samples.
2. If residual disease is detected in samples, characterise the single cell (sc) clonal architecture, epigenome and transcriptome and determine the leukemic stem cell content of the residual AML.
3. Perform an unbiased sc transcriptomic analysis of innate and acquired immune cells in BM, and peripheral blood (PB).
4. Test functional differences in comparable immune cells.