Implementing a Functional Precision Medicine Tumor Board for Acute Myeloid Leukemia

Abstract

We generated ex vivo drug-response and multiomics profiling data for a prospective series of 252 samples from 186 patients with acute myeloid leukemia (AML). A functional precision medicine tumor board (FPMTB) integrated clinical, molecular, and functional data for application in clinical treatment decisions. Actionable drugs were found for 97% of patients with AML, and the recommendations were clinically implemented in 37 relapsed or refractory patients. We report a 59% objective response rate for the individually tailored therapies, including 13 complete responses, as well as bridging five patients with AML to allogeneic hematopoietic stem cell transplantation. Data integration across all cases enabled the identification of drug response biomarkers, such as the association of IL15 overexpression with resistance to FLT3 inhibitors. Integration of molecular profiling and large-scale drug response data across many patients will enable continuous improvement of the FPMTB recommendations, providing a paradigm for individualized implementation of functional precision cancer medicine. Significance: Oncogenomics data can guide clinical treatment decisions, but often such data are neither actionable nor predictive. Functional ex vivo drug testing contributes significant additional, clinically actionable therapeutic insights for individual patients with AML. Such data can be generated in four days, enabling rapid translation through FPMTB. See related commentary by Letai, p. 290. This article is highlighted in the In This Issue feature, p. 275

Integrative analysis of drug response and clinical outcome in acute myeloid leukemia

“…This analysis revealed PEAR1 to perform equivalently to LSC17 both in the young subset and across all age groups (Figure S6). Finally, to validate the prognostic significance of PEAR1 using independent patient cohorts, we examined the capacity of PEAR1 expression to stratify overall survival using a dataset from Malani and coworkers as well as from The Cancer Genome Atlas (TCGA) (Cancer Genome Atlas Research et al, 2013;Malani et al, 2022). We found that elevated PEAR1 expression conferred shortened overall survival in a strongly significant manner in both datasets (Figures S7A and S7B).…”

Application of precision medicine in clinical routine in haematology—Challenges and opportunities

“…These systems biology data sets can readily be generated from both prospective fresh samples and viably frozen biobanked samples with good technological success rates. In one of the recent studies on AML, actionable drugs were found for 97% of the 252 included patient samples [123]. The same study also suggested individually tailored therapies for 37 relapsed or refractory AML patients and reported that 59% of the patients had objective responses, which are praising for the added value of the FPM approach.…”

“…To exclude general toxicity and to provide for disease selectivity, calculation of the difference to a control sample, such as healthy bone marrow, is often included in the hit scoring [117,121]. Viability-based FPM has been used to profile drug responses and to create large cohorts of leukaemia cases often including molecular omic profiling [34,122,123]. These systems biology data sets can readily be generated from both prospective fresh samples and viably frozen biobanked samples with good technological success rates.…”

Early response evaluation by single cell signaling profiling in acute myeloid leukemia

“…2 However, risk stratifications that included clinical and biological information, and are under discussion. 16 Functional analyses of drug sensitivity and signaling responses are suggested, 14,[17][18][19] but based on our previous observations of protein and gene expression hours after start of chemotherapy, 11,12 we hypothesize that early chemotherapy-induced alterations in intracellular signaling networks may be a more accurate predictor of long-term therapy response. Here, we have employed mass cytometry to investigate intracellular signaling networks in peripheral blood (PB) samples from 32 newly diagnosed AML patients during the first 24 hours of standardized induction chemotherapy.…”